NZ622081B2 - Estra-1,3,5(10),16-tetraene-3-carboxamide derivatives, process for preparation thereof, pharmaceutical preparations comprising them, and use thereof for production of medicaments - Google Patents

Estra-1,3,5(10),16-tetraene-3-carboxamide derivatives, process for preparation thereof, pharmaceutical preparations comprising them, and use thereof for production of medicaments Download PDF

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NZ622081B2
NZ622081B2 NZ622081A NZ62208112A NZ622081B2 NZ 622081 B2 NZ622081 B2 NZ 622081B2 NZ 622081 A NZ622081 A NZ 622081A NZ 62208112 A NZ62208112 A NZ 62208112A NZ 622081 B2 NZ622081 B2 NZ 622081B2
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estra
methyl
hydrogen
represent
carbonyl
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NZ622081A (en
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Naomi Barak
Ulrich Bothe
Matthias Busemann
Oliver Martin Fischer
Isabella Gashaw
Ingo Hartung
Tobias Marquardt
Andrea Rotgeri
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Bayer Intellectual Property Gmbh
Bayer Pharma Aktiengesellschaft
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Publication of NZ622081B2 publication Critical patent/NZ622081B2/en

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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
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    • A—HUMAN NECESSITIES
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed

Abstract

Disclosed herein are estra-1,3,5(10),16-tetraene-3-carboxamide derivatives of formula I where the substituents are as defined herein. The compounds are AKR1C3 inhibitors and are intended for the use for treatment and/or prophylaxis of diseases and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of bleeding problems and endometriosis. Specific examples of the compounds of formula I include 4-[({[17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]carbonyl}amino)methyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylic acid and N-methyl-N-{[17-(3-pyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]carbonyl}-B-alanine. treatment and/or prophylaxis of diseases, especially of bleeding problems and endometriosis. Specific examples of the compounds of formula I include 4-[({[17-(5-fluoropyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]carbonyl}amino)methyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylic acid and N-methyl-N-{[17-(3-pyridin-3-yl)estra-1,3,5(10),16-tetraen-3-yl]carbonyl}-B-alanine.

Description

,3,5§101,16-tetraene—3-carboxamide derivatives, process for preparation thereof, pharmaceutical preparations comprising them, and use thereof for production of medicaments The invention relates to AKRl C3 tors and to processes for their preparation, to their use for the ent and/or prophylaxis of diseases and also to their use for preparing medicaments for the ent and/or prophylaxis of diseases, in particular bleeding disorders and endometriosis.
AKRlC3 is a multifunctional enzyme and catalyses inter alia the reduction of 4-androstene- 3,17-dione (a weak androgen) to testosterone (a potent androgen) and of oestrone (a weak oestrogen) to 17B-oestradiol (a strong oestrogen). In addition, the reduction of prostaglandin (PG) H2 to PGFZu and PGD2 to 9a,11B-PGF2 is inhibited (T. M. Penning et. al., 2006, 'Aldo- keto reductase (AKR) 1C3: Role in prostate e and the development of specific inhibitors', Molecular and Cellular inology 248(1-2), 182 -l91).
The local formation of oestradiol (E2) plays a central role in the initiation and progression of breast cancer disorders and endometriosis. Reduction of the tissue concentrations of oestrogens and in particular of oestradiol is achieved by eutic administration of aromatase inhibitors (to inhibit the formation of oestrogens from androgens) and of sulphatase tors (to block the formation of oestrone from oestrone sulphate). However, both therapeutic approaches have the disadvantage that systemic oestrogen trations are radically reduced (A. Oster et. al., J. Med. Chem. 2010, 53, 8176—8186). Recently, it has been demonstrated experimentally that endometriotic lesions are capable of synthesizing oestradiol locally (B. Delvoux et al., J Clin Endocrinol Metab. 2009, 94, 3). For the subtype of ovarial endometriosis, an overexpression of AKR1C3 mRNA has been described (T. Smuc et al., Mol Cell Endocrinol. 2009 Mar 25; 301(1-2): 59-64).
There is a great need to identify novel tors of the enzyme aldo-keto reductase 1C3 (AKR1C3) (synonyms: type 5 17B-hydroxysteroid dehydrogenase or prostaglandin F synthase), since inhibitors have potential for the treatment of hormone—dependent disorders such as, for example, endometriosis, but also for the treatment of hormone-independent disorders (M.C. Byrns, Y. Jin, T.M. Penning, Journal of Steroid Biochemistry and Molecular Biology (2010); A. L. ng et. al., Cancer Res 64(5), 810). In addition to endometriosis, this also includes prostate cancer (K. M. Fung et al., Endocr Relat Cancer 13(1), 0), prostate hyperplasia (R. O. Roberts et al., Prostate 66(4), 392-404), endometrial carcinoma (T. L. Rizner et al., Mol Cell Endocrinol 2006 248(1-2), 126-135), Page 1 2012/068803 polycystic ovary syndrome (K. Qin et al., J Endocrinol Metab 2006, 91(1), 270-276), lung carcinoma (Q. Lan et a1., Carcinogenesis 2004, 25(11), 2177-2181), non-Hodgkin lymphoma (Q. Lan et a1., Hum Genet 2007, 121(2), 161-168), hair loss (L. Colombe et a1., Exp Dermatol 2007, 16(9), 9), adiposity (P. A. Svensson et a1., Cell Mol Biol Lett 2008, 13(4), 599- 613), bladder carcinoma (J. D. Figueroa, ogenesis 2008, 29(10), 1955-1962), chronic myeloid leukaemia (J. Birthwistle, Mutat Res 2009, 662(1-2), 67-74), renal cell carcinoma (J. T. Azzarello, Int J Clin Exp Pathol 2009, 3(2), 147-155), breast cancer (M. C. Byms, J Steroid Biochem Mol Biol 2010, 118(3), 177-187), premature sexual maturity (C. He, Hum Genet 2010, , 515-527) and c obstructive pulmonary disease (S. Pierrou, Am J Respir Crit Care 2007, 175(6), 577—586).
Some inhibitors of AKR1C3 are known (review: Joanna M Day, Helena J Tutill, Atul Purohit and l J Reed, Endocrine-Related Cancer (2008) 15, 665—692). A steroidal nce that has been described is, for example, EM-1404, which is based on the tiiene skeleton having a spirolactone unit in position 17 (F. Labrie et al. US Patent 6,541,463, 2003).
Further steroidal substances having a lactone unit are found in P. Bydal, Van Luu-The, F.
Labrie, D. Poirier, European Journal of Medicinal try 2009, 44, 632-644. Fluorinated oestratriene derivatives have been described in D. Deluca, G. Moller, A. Rosinus, W. Elger, A. Hillisch, J. Adamski, Mol. Cell. Endocrinol. 2006, 248, 218 - 224.
The compounds according to the invention are substances based on an -1,3,5(10),16- tetraene on substituted by an aromatic heterocycle in position 17 and an aminocarbonyl group in position 3. S. B. Barrie et al. US 5604213 describe 17-(3-pyridyl)estra-1,3,5(l0),16- tetraenol derivates as 17a-hydroxylase/C17-20 lyase (Cypl7A1) inhibitors. In particular, the substance pyridyl)estra-1,3,5(10),16-tetraenol is reported. However, US 5604213 does not describe any l7-(3-pyridyl)estra-1,3,5(10),16-tetraene derivatives substituted by an aminocarbonyl group in the tion. The compounds according to the invention claimed here additionally have a carboxyl group as fimctional group, resulting in a further structural Page 2 R2 N R6 CH H H R3 N R4 in which X and Y both represent a C-H group or one of X and Y ents a C-H group, while the other represents a nitrogen atom and Page 3 (followed by Page 3A) -C(CH3)2OH, -CONH2, -(C=O)NH-alkyl, N(CH3), -SO2NH2, -SO2NHCH3 or –SO2N(CH3)2; provided that when one of X and Y represents a C-H group and the other represents a nitrogen atom, at least one of R1 and R2 is hydrogen; and Page 3A (followed by Page 4) R3 and R4 represent hydrogen or one of R3 and R4 represents hydrogen, while the other represents y, fluorine, methoxy or ethoxy , Page 4 (followed by Page 4A) Page 4A wed by Page 5) and their pharmaceutically acceptable salts, solvates and solvates of the ceutically acceptable salts.
Page 5 in which represents hydrogen, fluorine, ne, nitrile, methoxy, ethoxy, romethoxy, methyl, ethyl, trifluoromethyl, -(C=O)CH3 and R3 and R4 represent hydrogen or R3 represents hydroxy and R4 represents hydrogen or R3 represents hydrogen and R4 represents hydroxy and R5 ents hydrogen or fluorine and represents hydrogen or C 1-C4-alkyl and 1 5 represents -CRaRb—COOH where R2! and Rb ndently of one another represent hydrogen, methyl or ethyl or Ra and Rb together represent -(CH2)n- where n = 2, 3, 4 or 5 or Ral represents hydrogen and Rb together with R7 represents ~(CH2)n- where n=3or4or represents -CR°Rd-CReRf-COOH where R°, Rd, Re, Rf represent hydrogen or Page 6 2012/068803 R°, R‘l represent hydrogen and R°, Rf independently of one another represent , ethyl or together represent ~(CH2)n- where n = 2, 3, 4, 5 or -CH2CH2-O-CH2CH2- 01' Rc represents methyl or ethyl and Rd, Re and Rf represent hydrogen or R° and Re together ent -(CH2),.- where n = 1, 2, 3 or 4 and Rd and Rf represent hydrogen or represents -CH2-CH2-CHRg-COOH where Rg represents hydrogen or Rg and R7 together represent —CH2CH2- and their salts, solvates and solvates of the salts.
The invention also provides compounds of the formula (II) and the formula (III) in which represents hydrogen, fluorine, chlorine, nitrile, methoxy, romethyl and R3 and R4 represent hydrogen or R3 represents y and R4 represents hydrogen or R3 represents hydrogen and R4 represents hydroxy and represents hydrogen or e and R7 represents hydrogen, methyl or ethyl and represents -CRaRb-COOH where R3 and Rb independently ofone another represent en, methyl or ethyl or Ra represents hydrogen and Rb together with R7 represents —(CH2)n- where n = 3 or 4 or represents -CR°Rd-CReRf-COOH where R°, Rd, Re, Rf represent hydrogen or Page 7 R°, Rd represent hydrogen and Re, Rf independently of one another represent methyl or ethyl or er represent -(CH2)n- where n = 2, 4, 5 or represent -CH2CH2-O-CH2CH2- or R° represents methyl and Rd, Re and Rf represent hydrogen or Rc and Re together represent -(CH2),.- where n = 3 or 4 and Rd and Rf represent hydrogen or represents H2-CHRg-COOH where Rg represents en or R3 and R7 together represent -CH2CH2- and their salts, solvates and solvates of the salts.
Moreover, the invention provides compounds of the formula (II) and the formula (III) in which represents hydrogen, fluorine, y, trifluoromethyl and R3 and R4 represent hydrogen or R3 represents hydroxy and R4 represents hydrogen or R3 represents hydrogen and R4 represents hydroxy and represents hydrogen or fluorine and represents hydrogen or methyl and represents -CRaRb—COOH where R‘1 and Rb independently of one another represent hydrogen or methyl or Ra ents en and Rb together with R7 represents —(CH2)3- or represents -CR°Rf-COOH where RC, Rd, Re, Rf represent hydrogen, or Page 8 R° and Rd represent hydrogen and Re and Rf represent methyl or together ent -(CH2)n- where n = 2 or 4 or represent -CH2CH2—O-CH2CH2- or R0 represents methyl and Rd, R° and Rf represent hydrogen or Rc and Re together represent ~(CH2)3- and Rd and Rf represent hydrogen or ents —CH2-CH2-CHRg-COOH where Rg represents hydrogen or RE and R7 represent -CH2CH2- and their salts, solvates and solvates of the salts.
Furthermore, the invention provides the compounds 17-(5-fluoropyridinyl)estra-1,3 ,5(1 0),1 6-tetraeny1]carbony1 } amino)- methy1]-3,4,5,6-tetrahydro-2H-pyrancarboxy1ic acid N-{[17-(5-fluoropyridinyl)estra-1,3,5(10),]6-tetraeny1]carbony1}-N-methyl-,B- alanine 1-[({[17-(5-fluoropyridinyl)estra-1,3 ,5(10),]6-tetraeny1]carbonyl}amino)- methyl]cyclopropan- l -carboxylic acid l-[({[17-(5-fluoropyridiny1)estra-1,3,5(10),16-tetraen-3—y1]carbony1}amino)- methy1]cyclopentanecarboxylic acid 3-({[17-(5-fluoropyridinyl)estra-1 ,3,5(10),16-tetraen—3-y1]carbonyl}amino)-2,2- dimethylpropanoic acid -(5-flu0ropyridinyl)estra-l,3,5(10),16-tetraenyl]carbonyl}piperidine—4- carboxylic acid N—{[17-(5-fluoropyridin-3—y1)estra-1,3,5(10),]6-tetraeny1]carbony1} alanine 4-({[17-(5-fluoropyridin-3 -yl)estra-1,3 ,16-tetraen-3 -yl] carbonyl} amino)butanoic acid N-{[17-(5-fluoropyridiny1)estra-1,3,5(10),l6-tetraenyl]carbonyl}-fl-alanine N- {[17-(5-fluoropyridin—3-y1)estra-l ,3 ,5(1 0),] 6-tetraen-3 -yl]carbony1 } glycine (1R*,2S*)({[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraen-3 -yl]carbonyl } - amino)cyclopentane—l -carb0xylic acid Page 9 (S)-3 -( {[1 7-(5-fluoropyridinyl)estra-l ,3 ,l 6-tetraen-3 -y1] carbonyl } amino)- butanoic acid (R)( {[1 7-(5-fluoropyridinyl)estra-1 ,3,5(10), l 6—tetraenyl]carbonyl} amino)- butanoic acid 3-({[17-(5-methoxypyridinyl)estra-1,3,5(10),16-tetraeny1]carbony1}amino)-2,2- dimethylpropanoic acid N—{[17-(5-methoxypyridiny1)estra-1,3 ,16-tetraenyl]carbonyl}-,B-a1anine N-{[17-(5-methoxypyridiny1)estra-1,3 ,5(1 tetraenyl]carbonyl}-N-methyl-fl- alanine N- {[17-(pyrimidinyl)estra— 1 ,3 1 6-tetraenyl]carbonyl} -,B-alanine , 5(10), 4-({[17-(pyrimidinyl)estra-1,3 , 5(1 0),l 6-tetraeny1]carbonyl } amino)butanoic acid N-methyl-N- { [ l 7-(pyrimidiny1)estra-l ,3 ,5(1 0),1 6-tetraenyl]carbonyl } -fl-alanine 2,2-dimethy1({[17-(pyrimidinyl)estra—l,3,5(10),16-tetraen—3-yl]carbony1}- amino)propanoic acid N-( { 1 7-[5-(tfifluoromethyl)pyridin-3 tra-1,3, 5(10), 1 6-tetraenyl } carbonyl)—,B- alanine N-methyl-N-({1 7-[5-(trifluoromethyl)pyridin-3 -yl]estra-1 ,3 ,5(] 0), l 6-tetraen-3 -yl } - carbonyl)—fl-alanine N-{[17-(5-fluoropyridiny1)estra—1,3,5(10),]6-tetraenyl]carbonyl}-L-proline N—{[17-(5-fluoropyridinyl)estra-1,3,5(10),]6-tetraenyl]carbony1}-D-proline 4-( {[1 oro-l7-(5-fluoropyridiny1)estra-1,3,5(10),l6-tetraenyl]carbonyl}- amino)butanoic acid N-{[17-(5-fluoropyridinyl)-lSa-hydroxyestra-l,3,5(10),1 6-tetraenyl]carbonyl} - N-methyl-fl-alanine N- {[ l 7-(5 -fluoropyridin—3 ~yl)-15,B-hydroxyestra—1,3 ,5(1 O),1 6-tetraen-3 -y1]carbonyl } - N-methyl-fl-alanine hyl—N—{[l7-(6-methy1pyridazinyl)estra—1 ,3 ,5 (1 0), l 6-tetraen-3 -yl]carbonyl} - fl-alanine N—methyl-N—{[17-(3-pyfidinyl)estra-1,3,5(10),16-tetraenyl]carbony1}-fl-alanine Page 10 7-(5-methoxypyridin-3 -yl)estra-1,3 ,5(10),16-tetraenyl]carbonyl}amino)- butanoic acid and their salts, solvates and solvates of the salts.
It has been found that the estra-l,3,5(10),16-tetraene-3—carbonylamino derivatives provided by the invention act as AKRl C3 inhibitors. For the major part of the structural range claimed, these substances show strong inhibition of AKRl C3 in vitro (ICso values of less than 50 nM) and predominantly even IC50 values < 20 nM. In addition, these derivatives have an only very low inhibition of Cyp17A1, if any.
Compounds according to the ion are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds of the formulae mentioned below comprised by formula (I) and their salts, solvates and solvates of the salts and the compounds mentioned below as working examples and comprised by formula (I) and their salts, solvates and solvates of the salts, provided the compounds mentioned below and comprised by formula (I) are not already salts, solvates and solvates of the salts.
Depending on their structure, the compounds according to the invention can exist in stereoisomeric forms (diastereomers). In compounds of the formula (I), stereocentres can be present in radical R8 (and, if R7 and R8 together form a cycle, also in this . Accordingly the invention comprises the diastereomers and their respective es. From such mixtures of diastereomers, the isomerically uniform components can be isolated in a known .
If the compounds according to the ion can be present in tautomeric forms, the present invention comprises all tautomeric forms.
Preferred salts in the t of the present invention are logically acceptable salts of the compounds according to the invention. However, the invention also comprises salts which for their part are not suitable for pharmaceutical applications, but which can be used, for example, for the isolation or ation ofthe compounds according to the invention.
Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, acetic acid, formic acid, roacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, c acid, maleic acid and benzoic acid.
Page 11 Physiologically acceptable salts of the compounds according to the invention also e salts of customary bases, such as, by way of e and by way of preference, alkali metal salts (for example sodium salts and potassium salts), alkaline earth metal salts (for example calcium salts and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procain, dibenzylamine, N- methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
In the t of the invention, solvates are those forms of the compounds according to the invention which, in the solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a specific form of the solvates where the coordination is with water. In the context of the present invention, red solvates are hydrates. er, the present invention also comprises prodrugs of the compounds according to the invention. The term “prodrugs” includes compounds which for their part may be biologically active or inactive but which, during the time they spend in the body, are converted into compounds according to the invention (for example metabolically or hydrolytically).
In the context of the present invention, unless specified differently, the substituents have the following meanings: glfig-Alkyl represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, by way of example and by way of preference methyl, ethyl, propyl, butyl, isopropyl, tert- butyl, yl.
Qifig—Cycloalkyl represents a cycloalkyl group having 3 to 6 carbon atoms, where the ring may also be lly unsaturated, by way of example and by way of preference cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The invention furthermore provides ses for preparing the nds of the formula (I) ing to the invention. The preparation of the compounds (I) according to the invention can be illustrated by the sis schemes below: Some of the compounds according to the invention can be prepared starting with methyl 17- oxoestra—1,3,5(10)—trienecarboxy1ate, which is known from the literature (Steroids, 1995, 60, 3, 299 — 306) (synthesis scheme 1): The conversion into Intermediate 1 is carried out by using trifluoromethanesulphonic 'de or s(trifluoromethanesulphonyl)aniline in the presence of a base such as Page 12 pyridine, methylpyridine or 2,6-di-tert-buty1pyridine or in the presence of a tertiary amine such as triethylamine or diisopropylethylamine, or by using alkali metal hexamethylsilazanes or lithium diisopropylamide (LDA) (J. Med. Chem, 1995 2463 — , 38, 2471, J. Org. Chem, 1985, 50, 1990 — 1992, JACS, 2009, 13], 9014 — 9019, Archiv der Pharmazie (Weinheim, Germany), 2001, 334, 12, 373 - 374). Preference is given to the reaction with trifluoromethanesulphonic anhydride in the presence of 2,6-di-tert-butylpyridine in dichloromethane.
The Intermediates 2 are ed using the Suzuki reaction, which is known to the person skilled in the art. To this end, Intermediate 1 is reacted with a nitrogen-containing aromatic boronic acid, a boronic ester such as, for e, a boronic acid le ester, an MIDA boronate (D. M. Knapp et al. J. Am. Chem. Soc. 2009, 131, 6961) or with a trifluoroborate salt (G. A. Molander et al., J. Org. Chem. 2009, 74, 973). Suitable catalysts are a large number of palladium-containing catalysts such as, for example, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladi1nn(ll) dichloride or [1,3-bis(2,6-diisopropylphenyl)imidazo1y1idene](3-chloropyridyl)palladium(II) dichloride (CAS 0). Alternatively, it is possible to use a palladium-containing source such as, for example, palladium(II) acetate, ium(II) chloride or Pd(dba)2 in combination with a phosphorous-containing ligand such as, for example, triphenylphosphine, SPhos (D. M.
Knapp et. al., J. Am. Chem. Soc. 2009, 131, 6961) or RuPhos (G. A. Molander, J. Org. Chem. 2009, 74, 973). The c acids are preferably reacted in the ce of tetrakis(triphenylphosphine)palladium(0) or [l,3-bis(2,6-diisopropylphenyl)imidazol e](3-chloropyridyl)palladium(lI) dichloride.
The Intermediates 3 are prepared by hydrolysis of the methyl ester according to methods known to the person skilled in the art. To this end, Intermediate 2 is, in a solvent such as tetrahydrofuran (THF), methanol or dimethyl sulphoxide (DMSO) or in a mixture ofmethanol and THF, admixed with aqueous sodium ide solution or an aqueous lithium hydroxide solution. If required, the mixture is heated. The reaction in THF and methanol in the presence of aqueous sodium hydroxide solution or aqueous lithium ide solution at 40°C is preferred.
The preparation of the exemplary compounds is carried out in two steps starting with Intermediates 3 by an amide coupling with an ester of an amino acid and by subsequent Page 13 conversion of the carboxylic ester into the carboxylic acid. Suitable for the amide ng (Step A) are reagents known to the person skilled in the art such as, for example, N,N’- dicyclohexylcarbodiimide (DCC), N-[3-(dimethy1amino)propyl]-N'-ethy1carbodiimide hydrochloride (EDC) [CAS 259528] or HATU (O-(7-azabenzotriazol-l-y1)-N,N,N’,N’- tetramethyluronium hexafluorophosphonate. Additionally, it is also possible to employ, as additives, reagents such as lH-benzotriazol-l-ol hydrate (HOBt hydrate [CAS 1233339]) or 4-dimethylaminopyridine (DMAP). Suitable for use as bases are, for example, pyridine, triethylaminc or diisopropylethylamine. Preference is given to the reaction using EDC, HOBt hydrate and triethylamine. For the conversion of the ylic ester into the carboxylic acid (Step B), it is possible to use — if the ester is, for example, a methyl, ethyl or benzylester — ysis methods as described for the preparation of Intermediate 3. If the ester is a tertbutyl carboxylate, this can be converted into the carboxylic acid by methods known to the person skilled in the art, such as, for example, by reaction with trifluoroacetic acid in dichloromethane or form or by reaction with hydrogen de in 1,4-dioxane. The reaction with roacetic acid in dichloromethane is preferred.
Page 14 // F 0’ \ CH3 \0 F Subset of the exemplary nds where R3, R4, R5 = H Synthesis scheme 1 A subset of the compounds of the formula (1) according to the invention where R5 = F and R6 = H can be prepared as described in synthesis scheme 2: Using acetic ide and pyridine in the presence of 4-dimethylaminopyridine (DMAP) in dichloromethane, 3,11a-dihydroxyestra-l,3,S(10)-trienone is converted into Intermediate 4. The conversion into Intermediate 5 is carried out using sodium bicarbonate in ol.
The reaction of Intermediate 5 with 1,1,2,2,3,3,4,4,4—nonafluorobutane-l-sulphony1 fluoride and potassium carbonate yields Intermediate 6, which is converted with palladium(II) acetate, Page 15 WO 45407 1,3-bis(diphenylphosphino)propane, triethylamine in methanol and DMSO in an autoclave under a carbon monoxide atmosphere into Intermediate 7. The conversion into Intermediate 8 is carried out using methods as described for the ation of Intermediate 1. The transformation of Intermediate 8 into Intermediate 9 is carried out using methods as described for the preparation of Intermediate 2. Using potassium carbonate and ol, Intermediate 9 is hydrolysed to give ediate 10. The transformation into Intermediate 11 is carried out using 1,8-diazabicyclo[5.4.0]undecene and 1,1,2,2,3,3,4,4,4—nonafluorobutane—1-su1phonyl fluoride in THF. The hydrolysis of Intermediate 11 to give Intermediate 12 is carried out using conditions as described for the preparation of Intermediate 3. Preference is given to the reaction in THF and methanol in the presence of s lithium hydroxide solution. The preparation of a subset of the exemplary compounds starting with Intermediate 12 is carried out analogously to the preparation of the exemplary compounds starting with Intermediate 3 as bed in synthesis scheme 1.
Page 16 o Subset of the Intermediate 11 0 Intermediate 12 exemplary nds where Synthesis scheme 2 R3, R4, R5 = H Page 17 A subset of the compounds of the formula (1) according to the invention having the substituent definition R3 =OH and R4=H or R3 =H and R4= OH can be prepared as illustrated in synthesis scheme 3. The reaction is carried out using microorganisms, for example certain le fungus strains allowing a regio- and selective hydroxylation. In this manner, it is possible, for example, to introduce hydroxyl groups into the 15-position of the steroid skeleton in a regio- and stereoselective manner. The resulting 15-OH derivatives are exemplary compounds for the e of the invention and can further also be modified further in subsequent chemical reactions.
Subset of the exemplary compounds of Subset of the exemplary compounds of the formula (I) where R3 and R4 = H the a (I) where R3 = OH and R4=H,orR3=Hand R4= OH Synthesis scheme 3 In an unforeseeable manner, the compounds according to the invention display a useful spectrum of pharmacological activity and ageous pharmacokinetic properties. They are therefore suitable for use as medicaments for the treatment and/or prophylaxis of diseases in humans and s. For the purpose of the present invention, the term “treatment” includes prophylaxis. The pharmaceutical efficacy of the compounds according to the ion can be explained by its action as AKR1C3 inhibitor. Accordingly, the nds according to the invention are ularly suitable for the treatment and/or prophylaxis of endometriosis, of e leiomyomas, of uterine ng disorders, of dysmenorrhoea, of prostate carcinoma, of prostate hyperplasia, of acne, of seborrhoea, of hair loss, of premature sexual maturity, of polycystic ovary syndrome, of breast cancer, of lung cancer, of endometrial carcinoma, of renal cell carcinoma, of bladder oma, of non-Hodgkin lymphomas, of chronic obstructive pulmonary disease (COPD), of adiposity or ofinflammatory pain.
Page 18 The present invention fithhermore provides the use of the compounds according to the ion for preparing a medicament for the treatment and/or laxis of disorders, in particular the disorders mentioned above.
The present invention furthermore provides a method for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an effective amount of the compounds according to the ion.
The t invention furthermore provides the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above.
The present invention furthermore provides the compounds according to the invention for use in a method for the treatment and/or prophylaxis of the disorders mentioned above.
The present invention furthermore provides medicaments comprising at least one compound according to the invention and at least one or more r active nds, in particular for the ent and/or prophylaxis of the disorders mentioned above. The ing suitable active compounds for combinations may be mentioned by way of example and by way of preference: selective oestrogen receptor modulators (SERMs), oestrogen receptor (ER) antagonists, aromatase inhibitors, 17B HSDl inhibitors, steroid sulphatase (STS) inhibitors, GnRH ts and nists, kisspeptin receptor (KISSR) antagonists, selective androgen receptor modulators (SARMs), androgens, Sa-reductase inhibitors, selective progesterone receptor modulators (SPRMs), gestagens, antigestagens, oral contraceptives, tors of mitogen activating protein (MAP) kinases and inhibitors of the MAP kinases kinases (Mkk3/6, Mekl/Z, Erkl/2), inhibitors of the protein kinases B (PKBa/B/y; Aktl/2/3), inhibitors of the phosphoinositide 3-kinases (PIBK), inhibitors of the cyclin-dependent kinase (CDKl/Z), inhibitors of the hypoxia-induced signal path (HIFlalpha inhibitors, activators of prolyl hydroxylases), e deacetylase (HDAC) inhibitors, glandin F receptor (FP) (PTGFR) antagonists and non-steroidal antiflammatory drugs (NSAle).
The invention also relates to pharmaceutical preparations comprising at least one compound of the general formula I (or physiologically able addition salts f with organic or inorganic acids) and the use of these compounds for preparing medicaments, in particular for the indications mentioned above.
The compounds can be used for the indications mentioned above, both afier oral and after parenteral administration.
Page 19 The compounds according to the invention can have systemic and/or local action. For this purpose, they can be administered in a le way, for example orally, parenterally, pulmonarly, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
For these routes of application, the compounds according to the invention can be stered in suitable dosage forms.
Dosage forms that function according to the prior art, with rapid and/or modified release of the compounds according to the invention, containing the nds according to the invention in crystalline and/or amorphisized and/or dissolved form, are suitable for oral administration, for example tablets (uncoated or coated tablets, for example with enteric coatings or coatings with delayed ution or insoluble coatings, which control the release of the compound according to the invention), tablets that disintegrate rapidly in the oral cavity or films/wafers, films/lyophylisates, capsules (for example elatin or soft-gelatin capsules), sugar-coated tablets, granules, pellets, powders, ons, suspensions, aerosols or solutions.
Parenteral administration can take place with avoidance of an absorption step (for e enously, intra-arterially, ardially, pinally or intralumbally) or with inclusion of absorption (for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). Suitable dosage forms for eral administration are inter alia injection and on preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders. le dosage forms for the other routes of administration are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops, solutions, and sprays; tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous sions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transderrnal therapeutic systems (such as, for example, patches), milk, , foams, dusting powders, implants, intrauterine systems, vaginal rings or stents.
The compounds according to the invention can be converted into the stated dosage forms.
This can take place in a manner that is known per se, by mixing with inert, non—toxic, pharmaceutically suitable auxiliaries. These auxiliaries include inter alia vehicles (for example microcrystalline cellulose, lactose, ol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium Page 20 dodecylsulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and l polymers (for example albumin), stabilizers (for example antioxidants such as, for example, ascorbic acid), colorants (for e inorganic pigments such as, for example, iron oxides) and taste and/or odour tants.
The present ion further relates to medicinal products comprising at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and their use for the purposes stated above.
In the case of oral stration, the amount per day is from about 0.01 to 100 mg/kg of body weight. The amount of a compound of the general formula I to be administered varies over a wide range and can cover every effective . Depending on the condition to be treated and the method of administration, the amount of the compound administered can be 0.01 - 100 mg/kg ofbody weight per day.
Nevertheless, it may optionally be necessary to deviate from the stated amounts, mainly depending on body weight, route of administration, dual response to the active substance, type of preparation and time point or interval in which administration takes place.
Thus, in some cases it may be sufficient to use less than the aforementioned minimum amount, whereas in other cases the stated upper limit must be exceeded. In the case of administration of relatively large amounts, it may be advisable to divide these into several individual doses throughout the day.
The percentages in the following tests and examples are, unless stated otherwise, tages by weight; parts are parts by weight. Proportions of solvents, dilution ratios and information about concentration for liquid/liquid ons relate in each case to volume.
Page 21 List of abbreviations, chemistry Abbreviations and acronyms: DMAP 4-Dimethylaminopyridine mamwe DMSO Dimethyl xide High-pressure, high-performance liquid chromatography LC-MS Liquid chromatography-coupled mass spectroscopy Electrospray mass spectroscopy Mass spectroscopy NMR Nuclear ic resonance spectroscopy Room temperature Trifluoroacetic acid Tetrahydrofuran Purification of the compounds according to the invention In some cases the compounds according to the invention could be purified by ative HPLC, for example using an autopurifier apparatus from Waters (detection of the compounds by UV detection and electrospray ionization) in combination with commercially available, prepacked HPLC columns (for example XBridge column (from Waters), C18, 5 pm, x 100 mm). The solvent system used was acetonitrile/water with addition of formic acid.
Further ves known to the person skilled in the art, such as, for example, ammonia, ammonium acetate or trifluoroacetic acid, may be used. Instead of acetonitrile, it is also possible to use, for example, methanol.
In some cases, the following method was used for ative HPLC separation: Page 22 WO 45407 System: Waters auto purification system: pump 2545, sample manager 2767, CFO, DAD 2996 ELSD 2424 S 0D XBrid-e C18 5 m100x30 mm A = H20 + 0.1% b volume formic acid 99% —B=Acetonitrile 0—1 min 1% B 1-8 min 1-99% B, 8-10 min 99% B AD scan range 210—400 nm —Zs ESI+ ESI- scan ran_e 160-1000 m/z Freeze-drying or vacuum centrifugation was used for removing the HPLC solvent mixture. If the resulting compounds are present as TFA salts or formate salts, they can be converted by standard tory procedures known to the person skilled in the art into the respective firee bases.
In some cases, the nds according to the invention could be purified by tography on silica gel. For this purpose, for example, prepacked silica gel cartridges (for example from Separtis, Isolute® Flash silica gel) in combination with the Flashmaster II chromatograh (Argonaut/Biotage) and chromatography solvents or solvent mixtures such as, for e, hexane, ethyl acetate and romethane and methanol were used.
Structural analysis of the compounds according to the invention: In some cases, the compounds according to the invention were ed by LC-MS: In some cases, the following analytical method was used: Instrument: Waters Acquity UPLC-MS SQD; column: Acquity UPLC BEH C18 1.7 mm; mobile phase A: water + 0.1% by volume of formic acid (99%), mobile phase B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml/min; temperature: 60°C; injection: 2 u]; DAD scan: 210-400 nm The following symbols are used in the NMR data of the compounds according to the invention: Page 23 =Triplet Centred multiplet Synthesis of the compounds ing to the invention: Intermediate 1 Methyl 17-{[(trifluoromethyl)sulphonyl]oxy}estra-l,3,5(10),16-tetraenecarboxylate CH I/ZQF 3.2 ml of trifluoromethanesulphonic anhydride were added dropwise to a e of 5.00 g (16.0 mmol) of methyl 17-oxoestra-1,3,5(10)-trienecarboxylate (Steroids, 1995, 60, 3, 299 — 306) in 100 m1 of dichloromethane and 5.3 m1 of -tert-butylpyridine, and the mixture was stirred at RT for 20 h. The mixture was carefully poured into 250 ml of saturated aqueous sodium bicarbonate solution and stirred for 40 min, the phases were separated, aqueous phase was extracted twice with dichloromethane and the combined organic phases were washed with saturated sodium bicarbonate solution and sodium chloride solution, dried over sodium sulphate and concentrated. Trituration with hexane gave 4.55 g of the title nd as a solid. 1H-NMR (300 MHz, CHLOROFORM-d): 6 [ppm]: 1.01 (s, 3H), 1.37 - 1.74 (m, 5H), 1.81 (td, 1H), 1.88 - 2.02 (m, 2H), 2.05 - 2.19 (m, 1H), 2.27 - 2.55 (m, 3H), 2.83 - 3.11 (m, 2H), 3.90 (s, 3H), 5.63 (dd, 1H), 7.32 (d, 1H), 7.68 - 7.90 (m, 2H).
Intermediate 2-a Page 24 Methyl 17-(5-fluoropyridinyl)estra-l,3,5(10),16-tetraenecarboxylate 8.00 g (2.25 mmol) of methyl 17-{[(trifluoromethy1)sulphony1]oxy}estra-1,3,5(10),l6- tetracne-S-carboxylate and 3.55 g (1.4 equiv.) of 5-fluoropyridineboronic acid were initially charged in 60 ml of toluene and 40ml of ethanol. 1.53 g (2.0 equiv.) of lithium chloride, 24 ml of 2M aqueous sodium ate solution and 1.04 g (5 mol%) of tetrakis(triphenylphosphine)palladi1un(0) were then added, and the mixture was heated at 100°C for 3.5 h. Water was added, the e was extracted three times with ethyl acetate and the ts were washed with saturated sodium bicarbonate solution and sodium chloride solution and concentrated. Purification by column chromatography on silica gel (hexane/ethyl acetate) gave 5.5 g (78% of theory) of the title compound. 1H-NMR (400 MHz, CHLOROFORM-d): 5 [ppm]= 1.06 (s, 3H), 1.47 - 1.63 (m, 1H), 1.63 - 1.78 (m, 3H), 1.84 (td, 1H), 1.98 - 2.06 (1n, 1H), 2.13 - 2.26 (m, 2H), 2.35 — 2.51 (1n, 3H), 2.98 (dd, 2H), 3.90 (s, 3H), 6.10 (dd, 1H), 7.32 — 7.44 (m, 2H), 7.76 - 7.86 (m, 2H), 8.36 (br. s., 1H), 8.48 (s, 1H).
Intermediate 2-b Methyl 17-(5-methoxypyridin—3—yl)estra-l,3,5(10),16-tetraenecarboxylate Page 25 Analogously to the preparation of intermediate 2-a, 2.00 g (4.50 mmol) of Intermediate 1 were reacted with 0.96 g (1.4 equiv.) of (S-methoxypyridinyl)boronic acid in the presence of 260 mg of tetrakis(tripheny1phosphine)palladium(0) at 100°C ght to give 1.4 g (76% of theory) of the title nd. 1H-NMR (300 MHz, CHLOROFORM-d): 5 [ppm]= 1.05 (s, 3H), 1.43 - 1.60 (m, 1H), 1.62 - 1.89 (m, 4H), 1.95 - 2.08 (m, 1H), 2.10 - 2.25 (m, 2H), 2.30 - 2.53 (m, 3H), 2.98 (dd, 2H), 3.88 (s, 3H), 3.90 (s, 3H), 6.00 - 6.08 (m, 1H), 7.16 - 7.22 (m, 1H), 7.35 (d, 1H), 7.75 - 7.83 (m, 2H), 8.20 (d, 1H), 8.28 (d, 1H).
Intermediate 2-c Methyl l7-(pyrimidin—5-yl)estra-l,3,5(10),16-tetraenecarboxylate Analogously to the preparation of Intermediate 2-a, 3.00 g (6.75 mmol) of Intermediate 1 were reacted with 1.17 g (1.4 equiv.) pyrimidin—S-ylboronic acid in the presence of 390 mg of tetrakis(triphenylphosphine)palladium(0) at 100°C ght to give 1.70 g (64% of theory) ofthe title compound. 1H-NMR (400 MHz, CHLOROFORM-d): 8 [ppm]= 1.06 (s, 3H), 1.47 - 1.59 (m, 1H), 1.65 - 1.80 (m, 3H), 1.85 (td, 1H), 1.98 - 2.06 (m, 1H), 2.12 - 2.25 (m, 2H), 2.36 - 2.53 (m, 3H), 2.98 (dd, 2H), 3.90 (s, 3H), 6.14 (dd, 1H), 7.35 (d, 1H), 7.76 - 7.85 (m, 2H), 8.76 (s, 2H), 9.09 (s, 1H).
Intermediate 2-d Methyl 17-[5-(trifluoromethyl)pyridinyl]estra-l,3,5(l0),]6-tetraenecarboxylate Page 26 Analogously to the preparation of Intermediate 2-a, 1.66 g (3.74 mmol) of Intermediate 1 were reacted with 1.00 g (1.4 ) of [5-(trifluoromethyl)pyridin—3-yl]boronic acid in the presence of 216 mg of tetrakis(tripheny1phosphine)palladium(0) at 100°C overnight to give 1.20 g (73% oftheory) of the title compound. 1H-NMR (300 MHz, CHLOROFORM-d): 8 [ppm]= 1.08 (s, 3H), 1.49 - 1.89 (m, 6H), 1.97 - 2.09 (m, 1H), 2.09 — 2.54 (m, 3H), 2.98 (dd, 2H), 3.90 (s, 3H), 6.15 (dd, — 2.28 (m, 2H), 2.35 1H), 7.36 (s, 1H), 7.77 - 7.85 (m, 2H), 7.88 (s, 1H), 8.83 (s, 2H).
Intermediate 2-e Methyl 17-(6-methylpyridazinyl)estra-l,3,5(10),16-tetraenecarboxylate ously to the preparation of ediate 2-a, 180 mg (3.74 mmol) of Intermediate 1 were reacted with 125 mg (1.4 equiv.) of 3-methyl-S-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridazine in the presence of 14 mg of bis(triphenylphosphine)palladium(II) chloride at 100°C. Aqueous work-up as described in the preparation of Intermediate 2-a gave 201 mg of a crude product which was used without r purification for preparing Intermediate 3-e.
Intermediate 2-f Page 27 Methyl 17-(pyridinyl)estra-1,3,5(10),]6—tetraenecarboxylate ously to the preparation of Intermediate 2-a, 500 mg (1.13 mmol) of Intermediate 1 were reacted with 194 mg (1.4 ) of pyridiny1boronic acid in the presence of 39 mg of bis(tripheny1phosphine)palladium(II) chloride at 100°C for 18 h. Aqueous work-up gave 462 mg of a crude product which was used without further purification for ing Intermediate 3-f.
Intermediate 3-a 17-(5-Fluoropyridinyl)estra-1,3,5(10),16-tetraenecarboxylic acid 372 mg (0.95 mmol) of Intermediate 2-a were initially charged in 50 m1 of THF and 3 ml of methanol. A solution of 120 mg of lithium hydroxide in 3 ml of water was added, and the mixture was stirred at RT for 18 h. Another 5 equiv. of lithium hydroxide were added and the mixture was stirred at RT for 24 h and at 40°C for 18 h. The mixture was d with water, acidified to pH 4 using 10% strength aqueous citric acid solution, ethyl acetate was added and the solid was filtered off, giving, after washing of the solid with ethyl acetate and water and drying, 153 mg (43% of theory) of the title compound. The organic phase of the filtrate was separated off and the aqueous phase was extracted twice with ethyl acetate. Washing of the ed organic phases with sodium chloride solution, drying over sodium sulphate and Page 28 concentration gave a residue which was triturated with diethyl ether. Drying gave a further 143 mg (40% of theory) of the title compound. 1H-NMR (300 MHz, DMSO'dé): 6 [ppm]= 0.99 (s, 3H), 1.38 - 1.78 (m, 5H), 1.83 - 1.97 (m, 1H), 2.05 - 2.21 (m, 2H), 2.25 - 2.43 (m, 3H), 2.89 (dd, 2H), 6.27 (dd, 1H), 7.36 (d, 1H), 7.58 - 7.72 (m, 3H), 8.43 (d, 1H), 8.49 (t, 1H).
Intermediate 3-b 17-(5-Methoxypyridinyl)estra-1,3,5(10),16-tetraene—3-carboxylic acid A solution of 1.4g (3.47 mmol) of methyl l7-(5-methoxypyridiny1)estra-1,3,5(10),16- tetraenecarboxylate in 30 m1 of THF, 4 m1 of methanol and 8.7 m1 of 2M aqueous sodium hydroxide solution were stirred at RT overnight and then warmed at 40°C for 8.5 h. The mixture was diluted with water, acidified to pH = 4 with 10% strength citric acid on and extracted three times with ethyl acetate, and the organic phases were washed with sodium chloride solution and concentrated. Trituration of the crude product with ether gave 1.2 g (89% of theory) of the title compound. 1H-NMR (300 MHz, DMSO-dg): 5 [ppm]= 0.98 (s, 3H), 1.34 - 1.81 (m, 5H), 1.84 - 1.97 (m, 1H), 2.03 - 2.19 (m, 2H), 2.21 — 2.43 (m, 3H), 2.89 (dd, 2H), 3.81 (s, 3H), 6.12 — 6.20 (m, 1H), 7.20 - 7.29 (m, 1H), 7.36 (d, 1H), 7.59 - 7.70 (m, 2H), 8.15 (d, 1H), 8.20 (d, 1H). ediate 3-c 17-(Pyrimidinyl)estra-1,3,5(10),16-tetraenecarboxylic acid Page 29 WO 45407 A e of 1.70 g (4.54 mmol) of methyl 17-(pyrimidinyl)estra-1,3,5(10),16-tetraene carboxylate, 40 ml of THF, 11.3 ml of 2M aqueous sodium hydroxide solution and 5 ml of methanol was stirred at RT overnight, then 40°C for 8.5 h and then at RT overnight. The mixture was diluted with water and acidified to pH = 4 with 10% strength citric acid solution, and ethyl acetate was added. The insoluble solid was filtered off and dried. This gave 1.3 g (79% of theory) of the title compound. 1H-NMR (300 MHz, DMSO-d6): 5 [ppm]: 0.99 (s, 3H), 1.39 - 1.79 (m, 5H), 1.84 — 1.97 (m, 1H), 2.06 — 2.21 (m, 2H), 2.26 - 6.33 (m, 1H), 7.36 (d, - 2.44 (m, 3H), 2.89 (dd, 2H), 6.28 1H), 7.59 - 7.69 (m, 2H), 8.83 (s, 2H), 9.04 (s, 1H), 12.7 (br. s., 1H).
Intermediate 3~d 17-[5-(Trifluoromethyl)pyridinyl]estra-l,3,5(10),16-tetraenecarboxylic acid 1.2 g of methyl 17-[5-(trifluoromethyl)pyridin—3-yl]estra-l,3,5(10),16-tetraenecarboxylate were initially charged in 12 ml of THF, a solution of 0.23 g of lithium hydroxide in 12 ml of water was added and the mixture was d at 40°C overnight. The mixture was diluted with water, acidified to pH = 4 with 10% strength citric acid solution and ted three times with ethyl acetate. The extracts were washed with sodium chloride solution and concentrated, Page 30 2012/068803 and the residue was triturated with diethyl ether. This gave 850 mg of the title compound as a solid. 1H-NMR (400 MHz, DMSO-ds): 8 [ppm]= 1.01 (s, 3H), 1.37 - 1.50 (m, 1H), 1.50 - 1.69 (m, 3H), 1.76 (td, 1H), 1.86 - 2.44 (m, 3H), 2.90 (dd, - 1.95 (m, 1H), 2.08 - 2.19 (m, 2H), 2.27 2H), 6.36 (dd, 1H), 7.36 (d, 1H), 7.61 - 7.68 (m, 2H), 8.04 (s, 1H), 8.82 - 8.86 (m, 1H), 8.90 (d, 1H), 12.7 (br. s., 1H).
Intermediate 3-e 17-(6-Methylpyridazin-4—yl)estra-l,3,5(10),16-tetraenecarboxylic acid 201 mg of methyl 17-(6-methy1pyridazinyl)estra-1,3,5(10),16—tetraenecarboxylate (crude product) were initially d in 3 ml of THF and 0.5 ml of methanol, 1.3 m1 of a 2M aqueous sodium hydroxide solution were added and the mixture was stirred at 40°C overnight. The mixture was diluted with water, acidified to pH = 4 with 10% th citric acid solution and extracted three times with ethyl acetate, and the extracts were concentrated.
Purification of the residue by preparative HPLC gave 42 mg of the title compound as a crude product.
C24H26N202 (374.5). MS-ES+ mass found: 374.20.
Intermediate 3-f 17-(Pyridinyl)estra-1,3,5(10),l6-tetraenecarboxylic acid Page 31 462 mg of methyl 17-(pyridinyl)estra-l,3,5(10),l6-tetraenecarboxylate (crude product) were dissolved in 4ml of THF and lml of methanol, 3 ml of a 2M aqueous sodium hydroxide solution were added and the mixture was d at 40°C overnight. The mixture was diluted with water and acidified to pH = 4 with 10% strength citric acid solution, and ethyl acetate was added. The insoluble solid that remained was filtered off, washed with water and ethyl acetate and dried under reduced re. This gave 375 mg (84% of theory) of the title compound.
C24H25N02 (359.47). MS-ES+ mass found: 359.00. 1H-NMR (300 MHz, DMSO-dé): 5 [ppm]= 0.99 (s, 3H), 1.35 - 1.78 (m, 6H), 1.84 - 1.96 (m, 1H), 2.03 - 2.18 (m, 2H), 2.21 - 2.44 (m, 4H), 2.89 (dd, 2H), 6.10 - 6.14 (m, 1H), 7.29 - 7.39 (m, 2H), 7.57 - 7.68 (m, 2H), 7.77 (dt, 1H), 8.42 (dd, 1H), 8.59 (d, 1H).
Intermediate 4 17-Oxoestra-1,3,5(10)-triene-3,1la-diyl ate At RT, 13.2 ml (4.0 ) of acetic anhydride were added dropwise to a solution of 10.0 g (34.9 mmol) of 3,1la-dihydroxyestra-l,3,5(10)—trienone in 100 m1 of dichloromethane, and the reaction mixture was cooled to 5°C. 14.1 ml of ne were then added dropwise, and afler 10 min the mixture was allowed to warm to RT and stirred for 4 h. A spatula tip of DMAP was added, and the mixture was stirred at RT for 72 h. The mixture was poured into 500 ml of water, the phases were separated, the aqueous phase was extracted with Page 32 dichloromethane and the ed organic phases were washed with 1M hydrochloric acid, water and sodium chloride solution, dried over sodium sulphate and concentrated. This gave 12.9 g (99% of theory) of a white solid.
IH-NMR (400 MHz, DMSO-d6): 8 [ppm]= 0.81 (s, 3H), 1.29 (t, 1H), 1.43 - 1.72 (m, 4H), 1.79 - 2.00 (m, 2H), 2.00 - 2.06 (m, 3H), 2.06 - 2.19 (m, 2H), 2.19 - 2.25 (m, 3H), 2.42 — 2.57 (m, superimposed by DMSO signal), 2.76 (t, 2H), 5.26 (td, 1H), 6.82 — 6.89 (m, 2H), 6.97 (d, 1H).
Intermediate 5 3-Hydroxyoxoestra-1,3,5(10)-trien-1la-yl acetate 14.6 g (5 equiv.) of sodium bicarbonate were added to 12.9 g (34.7 mmol) of l7-oxoestra- l,3,5(10)-triene-3,1la-diyl diacetate in 100 ml of methanol, and the mixture was stirred at RT overnight. 100 ml of water and 1 ml of 1M hydrochloric acid were added, and the e was d for 30 min. The e was extracted four times with ethyl acetate. A solid precipitated from the organic phase, which solid was filtered off with suction and dried. This gave 3.74 g (33% of ) of the title compound. In addition, 6.39 g (56% of theory) of the title compound were isolated by washing the organic phase with saturated sodium chloride solution, drying over sodium sulphate, concentration, trituration of the residue with ethyl acetate, filtration with suction and drying under d pressure.
]H-NMR (300 MHz, DMSO-d5): 6 [ppm]= 0.79 (s, 3H), 1.25 (t, 1H), 1.36 - 1.69 (m, 4H), 1.75 - 1.98 (m, 2H), 1.98 - 2.18 (m, 5H), 2.34 - 2.43 (m), 2.68 (t, 2H), 5.16 (td, 1H), 6.43 - 6.55 (m, 2H), 6.76 (d, 1H), 9.07 (s, 1H).
Intermediate 6 3-{[(1,],2,2,3,3,4,4,4-Nonafluorobutyl)sulphonyl]oxy}-l7-oxoestra-l,3,5(10)-trien-1la-yl acetate Page 33 12.8 g (3 equiv.) of potassium carbonate and 6.5 ml (1.2 equiv.) of l,1,2,2,3,3,4,4,4- nonafluorobutane-l-sulphonyl fluoride were added to a solution of 10.1 g (31 mmol) of 3- hydroxyoxoestra-1,3,5(10)-trien-1la-yl acetate in 20 m1 of THF, and the mixture was heated under reflux for 4h and stirred at RT for 18 h. Another 1ml of l,1,2,2,3,3,4,4,4- nonafluorobutane-l-su1phony1 fluoride was added, and the mixture was heated under reflux for 3 h. Water and saturated sodium chloride solution were added, the mixture was stirred for min, the phases were separated and the aqueous phase was extracted three times with in each case 50 m1 of ethyl acetate. The combined organic phases were washed twice with in each case 50 m1 of water and twice with 50 ml of saturated sodium chloride on, dried over sodium sulphate, filtered and concentrated. ation by column chromatography on silica gel (hexane/ethyl e) gave 18.1 g (96% of theory) of 3-{[(1,1,2,2,3,3,4,4,4- nonafluorobutyl)sulphonyl]oxy}-l 7-oxoestra-1 ,3,5(10)-trien-1 la-yl acetate. lH-NMR (400 MHz, DMSO-dé): 6 [ppm]: 0.85 (s, 3H), 1.26 - 1.37 (m, 1H), 1.47 - 1.76 (m, 4H), 1.83 — 2.47 (m), 2.59 (t, - 2.02 (m, 2H), 2.03 - 2.25 (m, 5H, contains s at 2.06 ppm), 2.41 1H), 2.77 - 2.95 (m, 2H), 5.29 (td, 1H), 7.15 (d, 1H), 7.23 - 7.29 (m, 2H). ediate 7 Methyl 1la-acetoxy-l7-oxoestra-1,3,5(l0)-trienecarboxylate Under argon, 10.0 g (16.4 mmol) of 3-{[(l,1,2,2,3,3,4,4,4-nonafluorobutyl)sulphonyl]oxy}- l7-oxoestra-1,3,5(lO)—tn'en-1la-yl acetate, 230 mg (6 mol%) of palladium(II) acetate and Page 34 440 mg (6 mol%) of 1,3-bis(diphenylphosphino)propane were initially charged in an autoclave, and 36 ml of methanol, 54 ml of DMSO and 6 m1 of triethylamine were added. The reaction mixture was flushed three times with carbon monoxide and stirred at RT at a carbon monoxide pressure of 7.5 bar for 30 min. The autoclave was then vented and evacuated, and the mixture was stirred at 70°C at a carbon monoxide pressure of 6.8 bar for 3.5 h. The e was concentrated and the residue was taken up in water and ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with 1M hloric acid and ted sodium bicarbonate solution, dried over sodium sulphate and concentrated. Purification of the residue by column chromatography on silica gel e/ethyl acetate) gave 5.96 g (98% of theory) of the title compound as a solid. 1H-NMR z, DMSO-d6): 5 [ppm]= 0.81 (s, 3H), 1.29 (t, 1H), 1.40 - 1.76 (m, 4H), 1.78 — 2.52 (m, obscured by - 2.00 (m, 2H), 2.00 - 2.21 (m, 5H, contains s at 2.03 ppm), 2.37 DMSO signal), 2.59 (t, 1H), 2.72 (s, 3H), 5.29 (td, 1H), 5.23 - 5.38 (m, - 2.93 (m, 2H), 3.79 1H), 7.08 (d, 1H), 7.68 - 7.75 (m, 2H).
Intermediate 8 Methyl lla-acetoxy-l7-{[(trifluoromethyl)sulphonyl]oxy}estra-l,3,5(10),16-tetraene carboxylate Analogously to preparation of lnterrnediate 1, 2.96 g (7.99 mmol) of methyl lla-acetoxy oxoestra-l,3,5(]0)-trienecarboxylate were converted in 5.13 g of the title compound as a crude product (contained residual -tert—butylpyridine). 1H-NMR (300 MHz, DMSO-d6): 8 [ppm]= 0.93 (s, 3H), 1.41 - 1.71 (m, 3H), 1.71 - 1.87 (m, 1H), 1.87 — 2.16 (m, 5H, contains 5 at 2.03 ppm), 2.16 - 2.40 (m, 2H), 2.67 (t, 1H), 2.74 - 2.93 (m, 2H), 3.79 (s, 3H), 5.34 (td, 1H), 5.75 — 5.82 (m, 1H), 7.03 (d, 1H), 7.67 - 7.75 (m, 2H).
Intermediate 9 Page 35 Methyl 1la-acetoxy-l7-(5-fluoropyridinyl)estra-1,3,5(l0),16-tetraenecarboxylate Analogously to Intermediate 2-a, 2.50 g (4.98 mmol) of methyl lla-acetoxy {[(trifluoromethyl)sulphonyl]oxy} estra-l ,3,5(10),16-tetraene-3—carboxylate were d with 981 mg (1.4 equiv.) of 5-fluoropyridine—3-boronic acid in the presence of 170 mg (5 mol%) of [1 (2,6-diisopropylphenyl)imidazolylidene](3-chloropyridyl)pa11adium(ll) dichloride ITM-IPr, CAS 9054590) at reflux temperature over a period of 5 h. This gave 2.62 g of the title compound as a crude product.
Intermediate 10 Methyl 17-(5-fluoropyridinyl)—lla-hydroxyestra-l,3,5(10),16-tetraenecarboxylate 4.0 g (5 equiv.) of potassium carbonate were added to 2.62 g (5.83 mmol) of methyl-lla- acetoxy—l7-(5-fluoropyridin—3-yl)estra-l,3,5(l0),16-tetraenecarboxylate in 40 m1 of methanol, and the mixture was stirred at RT for 3 h. The mixture was diluted with water and 1M hydrochloric acid and extracted three times with ethyl e. The combined organic phases were washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated. Column chromatography on silica gel (hexane/ethyl acetate) gave 1.19 g (50% oftheory) of the title compound.
Page 36 PCT/EP2012/O68803 1H-NMR (300 MHz, DMSO'dé, selected signals): 6 [ppm]= 0.95 (s, 3H), 1.40 - 1.61 (m, 3H), 2.78 — 4.92 (m, 1H), 6.26 (br. — 4.21 (m, 1H), 4.79 - 2.97 (m, 2H), 3.79 (s, 3H), 4.06 s., 1H), 7.59 - 7.74 (m, 3H), 8.07 (d, 1H), 8.39 - 8.54 (m, 2H).
Intermediate 11 Methyl llfl-fluoro-l7-(5-fluoropyridinyl)estra-l,3,5(10),16-tetraenecarboxylate 0.52 ml (1.65 equiv.) of 1,8-diazabicyclo[5.4.0]undec—7-ene and 0.58 ml (1.5 ) of 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulphony1 fluoride were added dropwise to an ice-cold solution of 531 mg (3.49 mmol) of methyl 17-(5—fluoropyridinyl)-1la-hydroxyestra- 1,3,5(10),l6-tetraenecarboxylate in 15 ml of THF, and the mixture was stirred with ice- bath cooling for 3 h. The e was concentrated and the product was purified by column chromatography on silica gel (hexane/ethyl acetate). This gave 747 mg (84% of theory) of the title compound as a crude product. 1H-NMR (300 MHz, DMSO-dé, selected s): 5 [ppm]= 2.86 — 2.97 (m, 2H), 5.57 — 5.83 (m, 1H), 6.26 — 6.32 (m, 1H), 7.45 — 7.53 (m, 1H), 7.65 - 7.78 (m, 3H), 8.39 - 8.53 (m, 2H).
Intermediate 12 l lfl-Fluoro(5-fluoropyridinyl)estra-1,3,5(10),]6—tetraenecarboxylic acid Page 37 ml of methanol and 442 mg of m hydroxide monohydrate in 5 m1 of water were added to a mixture of 862 mg (2.11 mmol) of methyl 1lfl—fluoro-l7-(5-fluoropyridinyl)estra- l,3,5(10),16-tetraenecarboxylate in 10ml of THF, and the mixture was stirred at room temperature overnight. Water was added, and the on mixture was adjusted to pH = 4 with 10% strength aqueous citric acid solution. The resulting precipitate was filtered off with suction, washed with ethyl acetate and dried. This gave 498 mg (60% of theory) of a white solid. 1H—NMR (500 MHz, DMSO'dfi): 8 [ppm]= 1.19 (s, 3H), 1.44 - 1.59 (m, 1H), 1.80 - 1.96 (m, 2H), 1.96 - 2.29 (m, 1H), 2.32 - 2.42 (m, 1H), 2.59 (td, 1H), 2.74 (dd, - 2.08 (m, 2H), 2.18 1H), 2.77 (br. s., 1H), 2.86 - 3.00 (m, 2H), 5.66 — 5.80 (m, 1H), 6.32 (dd, 1H), 7.48 (d, 1H), 7.65 — 7.78 (m, 3H), 8.47 (d, 1H), 8.54 (t, 1H).
Example 1 17-(5-Fluoropyridinyl)estra-1,3,5(10),16—tetraenyl]carbonyl}amino)methyl]- 6-tetrahydro-2H—pyrancarboxylic acid Step A: 100 mg (0.26 mmol) of l7-(5-fluoropyridiny])estra-1,3,5(10),16-tetraene carboxylic acid were initially charged in 1 m1 of DMF and 3 ml of THF. 119 mg (2.0 equiv.) of ethyl 4-(aminomethyl)-3,4,5,6—tetrahydro—ZH—pyrancarboxylate hydrochloride, 41 mg (2.0 equiv.) of l-hydroxy-lH-benzotriazole hydrate, 102 mg (2.0 equiv.) of 1-(3- dimethylaminopropy1)-3—ethylcarbodiimide hydrochloride and 0.11 ml of triethylamine were then added, and the e was stirred at RT overnight. m0.66 ml of a 2M aqueous sodium hydroxide solution and 0.50 ml of methanol were then added, and the mixture was stirred at RT ght. Water was added, and the reaction mixture was then acidified to a pH of 3-4 with a 10% strength aqueous citric acid solution.
The aqueous phase was extracted three times with ethyl acetate, the combined org. phases Page 38 were concentrated and the residue was purified by preparative HPLC (acetonitiile/water/fonnic acid). This gave 76 mg (55% of theory) of a solid.
FN204 (518.6). MS-ES+ mass found: 518.26. 1H NMR (300 MHz, DMSO'dfi, selected signals) 5 ppm 0.99 (s, 3 H), 1.36 - 1.99 (m, 10 H), 2.05 -— 3.76 (m, - 2.21 (m, 2 H), 2.25 - 2.44 (m, 3 H), 2.82 - 2.95 (m, 2 H), 3.39 (d, 2 H), 3.67 2 H), 6.25 — 6.29 (m, 1 H), 7.31 (d, 1 H), 7.49 - 7.60 (m, 2 H), 7.68 (dt, 1 H), 8.27 (t, 1 H), 8.43 (d, 1 H), 8.49 (s, l H), 12.5 (br. 5).
Example 2 N-{[17-(S-Fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-N-methyl-fl- alanine Step A: 1.62 g (1.0 equiv.) of l-hydroxy—lH—benzotriazole hydrate, 4.06 g (2.0 equiv.) of 1- (3-dimethy1aminopropyl)ethylcarbodiimide hydrochloride (EDC) and 4.4 ml of triethylamine were added to a mixture of 4.00g (10.6 mmol) of 17-(5-fluoropyridin yl)estra-1,3,5(10),16-tetraenecarboxy1ic acid and 3.38 g (2 equiv.) of tert—buty] N-methyl- ,B-alaninate in 100 m1 of THF and 5 m1 of DMF, and the mixture was stirred at RT for 18 h.
The mixture was d with water and extracted three times with ethyl acetate, and the extracts were washed with sodium de solution and trated. Purification of the residue with silica gel (hexane/ethyl acetate) gave 5.1 g of tert-butyl N-{[1 uoropyridin- 3-y1)estra—1,3,5(10),16-tetraeny1]carbonyl}-N-methyl-,B-alaninate (93% of theory) as a solid.
Step B: 1.00g (1.93 mmol) of tert-butyl N-{[17-(5-fluoropyridiny1)estra-1,3,5(10),l6- tetraen—3-yl]carbonyl}-N-methyl-,B-alaninate was initially charged in 15 ml of dichloromethane, 1.5 ml of trifluoroacetic acid were added and the mixture was stirred at 40°C overnight, poured into ice-water, d briefly and extracted three times with dichloromethane. The combined organic phases were washed with saturated sodium chloride Page 39 solution, filtered through a water-repelling filter and concentrated. Diethyl ether was added to the crude product, the mixture was stirred and filtered off with suction and the product was washed with diethyl ether and dried. This gave 0.79 g (89% of theory) of N-{[17-(5- fluoropyridin-3 -yl)estra-l ,3 ,5(1 0), 1 6-tetraen-3 -yl]carbonyl} -N—methyl-fl-alanine.
C23H31FN203 (462.6). MS-ES+ mass found: 462.23. 1H-NMR (300 MHz, DMSO-d6): 8 [ppm]= 1.00 (s, 3H), 1.33 — 1.79 (m, 5H), 1.82 - 1.99 (m, 1H), 2.08 — 2.21 (m, 2H), 2.21 — 2.88 (5H, contains s - 2.43 (m, 3H), 2.50 (s), 2.74 at 2.88 ppm), 3.36 - 3.71 (m), 6.27 (s., 1H), 6.99 - 7.16 (m, 2H), 7.28 (d, 1H), 7.68 (dt, 1H), 8.43 (d, 1H), 8.49 (s, 1H), 8.48 - 8.56 (m, 1H), 12.28 (br. s.). 1-[({ [17-(5-Fluoropyridinyl)estra-1,3,5(10),16-tetraenyl] carbonyl}amino)methyl]- cyclopropane-l—carboxylic acid Analogously to Example 1, 100 mg (0.26 mmol) of 17-(5-fluoropyridiny1)estra- 1,3,5(10),16-tetraenecarboxy1ic acid and 88 mg (2.0 equiv.) of methyl 1- (aminomethyl)cyclopropane-1—carboxy1ate hydrochloride were converted into 72 mg (57% of theory) of the title nd.
C29H31FN203 (474.6). MS-ES+ mass found: 474.23. 1H-NMR (300 MHz, 6): 5 [ppm]= 0.82 - - 0.90 (m, 2H), 0.95 1.06 (m, 5H), 1.33 1.81 (m, 5H), 1.56 (d, 3H), 1.84 - — 1.97 (m, 1H), 2.05 - 2.44 (m), 2.80 - 1.97 (m, 1H), 1.84 2.94 (m, 2H), 3.44 - 3.54 (m, 2H), 6.27 (s., 1H), 7.31 (d, 1H), 7.50 - 7.60 (m, 2H), 7.68 (dt, 1H), 8.18 (t, 1H), 8.43 (d, 1H), 8.49 (s, 1H), 12.3 (s, 1H).
Example 4 1-[({ [l7-(5—Fluoropyridin-S-yl)estra-1,3,5(10),]6-tetraenyl]carbonyl}amino)methyl]- cyclopentane-l-carboxylic acid Page 40 Analogously to Example 1 (step B was carried out at 50°C ght and after addition of a further 5 equiv. of 2M aqueous sodium hydroxide solution by stirring at 60°C overnight), 100 mg (0.26 mmol) of 17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenecarboxylic acid and 103 mg (2.0 equiv.) of methyl 1-(aminomethyl)cyclopentane—1-carboxylate hloride were converted into 63 mg (48% of theory) of the title compound.
C31H35FN203 (502.6). MS-ES+ mass found: . lIJI-NMR (400 MHz, DMSO—d6): 8 [ppm]= 0.99 (s, 3H), 1.36 — 1.66 (m), 1.73 (td, 1H), 1.81 - - 2.44 (m), 2.83 - 2.95 (m, 2H), 3.45 (d, 2H), 6.25 - 1.95 (m, 3H), 2.07 — 2.20 (m, 2H), 2.25 6.29 (m, 1H), 7.31 (d, 1H), 7.49 - 7.56 (m, 2H), 7.69 (dt, 1H), 8.14 (t, 1H), 8.43 (d, 1H), 8.49 (s, 1H), 12.2 (8).
Example 5 3-({[17-(5-Fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl} amino)-2,2- dimethylpropanoic acid ously to Example 1 (step B was carried out at 50°C overnight and after addition of a further 5 equiv. of 2M aqueous sodium hydroxide solution while stirring at 60°C overnight), 100 mg (0.26 mmol) of 17-(5-fluoropyridiny1)estra-1,3,5(10),16-tetraenecarboxylic acid Page 41 and 89 mg (2.0 equiv.) of methyl 3-amino-2,2-dimethy1propanoate hydrochloride were converted into 63 mg (50% of theory) of the title compound.
C29H33FN203 (476.6). MS-ES+ mass found: 476.25. 1H-NMR (400 MHz, DMSO-d6): 6 [ppm]= 0.99 (s, 3H), 1.06 (s, 6H), 1.36 - 1.66 (m, 4H), 1.73 (td, 1H), 1.86 - 2.45 (m, 3H), 2.84 - 2.92 (m, - 1.95 (m, 1H), 2.07 - 2.20 (m, 2H), 2.25 2H), 3.37 (d, superimposed by water signal), 6.25 - 7.57 (m, - 6.29 (m, 1H), 7.31 (d, 1H), 7.50 2H), 7.69 (dt, 1H), 8.15 (t, 1H), 8.43 (d, 1H), 8.49 (t, 1H), 12.2 (s).
Example 6 1-{[17-(5-Fluoropyridin—3-yl)estra—l,3,5(l0),l6-tetraeny11carbonyl}piperidine carboxylic acid Analogously to Examplel (step B was d out at 50°C over a period of 5 h), 100 mg (0.26 mmol) of 17-(5-fluoropyridinyl)ectra-1,3,5(10),]6-tetraenecarboxylic acid and 83 mg (2.0 equiv.) of ethyl piperidinecarboxylate were converted into 65 mg (50% of ) of the title compound.
C30H33FN203 ). MS-ES+ mass found: 488.25.
IH-NMR (400 MHz, DMSO'dé): 5 [ppm]= 1.00 (s, 3H), 1.33 - 1.96 (m, 10H), 2.03 - 2.22 (m, 2H), 2.24 - 2.43 (m, 3H), 2.79 - 2.94 (m, 3H), 3.02 (br. s., 1H), 3.57 (br. s., 1H), 4.26 (br. s., 1H), 6.25 - - 6.29 (1n, 1H), 7.00 - 7.11 (m, 2H), 7.29 (d, 1H), 7.69 (dt, 1H), 8.43 (d, 1H), 8.47 8.51 (m, 1H), 12.3 (5).
Example 7 N-{[17-(5-Fluoropyridinyl)estra-l,3,5(10),16-tetraenyl]carbonyl}methylalanine Page 42 Analogously to Examplel (step B was d out by heating at 50°C overnight and, afier on of a further 5 equiv. of 2M aqueous sodium hydroxide solution, stirring at 60°C overnight), 100 mg (0.26 mmol) of 17-(5-fluoropyridiny1)estra-1,3,5(10),16-tetraene ylic acid and 81 mg (2.0 equiv.) of methyl 3-amino-2,2-dimethy1propanoate hydrochloride were converted into 81 mg (66% of theory) of the title compound.
FN203 (462.6). MS-ES+ mass found: 462.23. 1H-NMR (300 MHz, DMSO-d6): 8 [ppm]= 0.99 (s, 3H), 1.39 (s, 6H), 1.4 - 1.82 (m), 1.86 - 1.98 (m, 1H), 2.05 - 2.43 (m, 2H), 2.20 - 2.50 (m), 2.83 - 2.94 (m, 2H), 6.27 (s, 1H), 7.31 (d, 1H), 7.52 - 8.53 (m, 1H), - 7.61 (m, 2H), 7.65 - 7.72 (m, 1H), 8.29 (s, 1H), 8.43 (d, 1H), 8.46 12.1 (5).
Example 8 4-({[l7-(5-Fluoropyridinyl)estra-l,3,5(10),l6-tetraenyllcarbonyl}amino)butanoic acid Analogously to Example 1, 100 mg (0.26 mmol) of 17-(5-fluoropyridinyl)estra- 1,3,5(10),l6-tetraenecarboxylic acid and 81 mg (2.0 equiv.) of methyl 4-aminobutanoate hydrochloride were converted into 58 mg (48% of theory) of the title compound.
C23H31FN203 (462.6). MS-ES+ mass found: 462.23.
Page 43 'H-NMR (300 MHz, DMSO-d6): 8 [ppm]= 0.99 (s, 3H), 1.39 - 1.78 (m, 7H), 1.83 - 1.99 (m, 1H), 2.05 — 2.50 (m, superimposed by DMSO signal), 3.1 — 3.4 (m, superimposed by water ), 2.79 - 7.59 (m, 2H), 7.67 (dt, 1H), - 2.98 (m, 2H), 6.26 (s., 1H), 7.31 (d, 1H), 7.52 8.32 (t, 1H), 8.43 (d, 1H), 8.49 (s, 1H), 12.0 (s).
Example 9 N-{[17-(5-Fluoropyridinyl)estra-1,3,5(10),]6-tetraenyl]carbonyl}-fl-alanine Analogously to Example 1, 100 mg (0.26 mmol) of 17-(5-fluoropyn'dinyl)estra— 1,3,5(10),16-tetraenecarboxylic acid and 81 mg (2.0 equiv.) of ethyl ,[J-alaninate hydrochloride were converted into 59 mg (50% of theory) of the title nd.
C27H29FN203 ). MS-ES+ mass found: 448.22. 1H—NMR (300 MHz, DMSO-d6): 6 [ppm]= 0.99 (s, 3H), 1.38 - 1.78 (m, 5H), 1.83 - 1.98 (m, 1H), 2.05 - 2.94 (m, - 2.21 (m, 2H), 2.25 — 2.44 (m, superimposed by DMSO signal), 2.80 2H), 3.35 - 3.51 (m, superimposed by water signal), 6.26 (s., 1H), 7.31 (d, 1H), 7.50 - 7.58 (m, 2H), 7.62 - 7.74 (m, 1H), 8.36 (t, 1H), 8.43 (d, 1H), 8.49 (s, 1H), 12.2 (s).
Example 10 N-{ [17-(5-Fluoropyridin-3—yl)estra-l,3,5(10),16-tetraenyllcarbonyl} glycine Page 44 Analogously to Example 1, 100 mg (0.26 mmol) of l7-(5-fluoropyridiny1)estra- 1,3,5(10),16-tetraenecarboxylic acid and 67 mg (2.0 equiv.) of methyl glycinate hydrochloride were converted into 58 mg (50% oftheory) of the title compound.
C26H27FN203 ). MS-ES+ mass found: 434.20. 1H-NMR (400 MHz, DMSO-d6): 8 [ppm]= 1.00 (s, 3H), 1.37 - 1.67 (m, 4H), 1.74 (td, 1H), 1.85 - 2.5 (m, superimposed by DMSO signal), 2.84 - 1.97 (m, 1H), 2.07 - 2.21 (m, 2H), 2.26 (d, 2H), 6.25 - 7.61 (m, 2H), 7.64 - - 2.94 (m, 2H), 3.86 - 6.29 (m, 1H), 7.34 (d, 1H), 7.55 7.72 (m, 1H), 8.43 (d, 1H), 8.49 (t, 1H), 8.64 (t, 1H), 12.5 (s).
Example 11 (1R*,2S*)({ [l7-(5-Fluoropyridinyl)estra-1,3,5(1 0),16-tetraenyl] carbonyl} amino)- cyclopentane-l-carboxylic acid Analogously to Example 1, 100 mg (0.26 mmol) of 17-(5—fluoropyridiny1)estra- 1,3,5(10),16-tetraenecarboxy1ic acid and 103 mg (2.0 equiv.) of (1R*,2S*)-ethy1 2- yclopentane—l-carboxylate hydrochloride were converted into 63 mg (49% of theory) of the title nd.
C30H33FN203 (488.6). MS-ES+ mass found: 488.25.
]H-NMR (300 MHz, DMSO-d6): 8 [ppm]: 1.00 (s, 3H), 1.39 - 1.66 (m, 5H), 1.68 - 1.96 (m, 7H), 2.02 - 2.21 (m, 2H), 2.24 - 2.41 (m), 2.78 - 2.98 (m, 3H), 4.42 — 4.57 (m, 1H), 6.27 (s., 1H), 7.30 (d, 1H), 7.46 - 7.58 (m, 2H), 7.68 (dt, 1H), 8.03 (d, 1H), 8.43 (d, 1H), 8.46 — 8.52 (m, 1H), 11.9 (3). e 12 (S)—3-({[l7—(S-Fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}amino)- butanoic acid Page 45 Analogously to Example 1 (in step B, an additional 5 equiv. of 2M aqueous sodium hydroxide solution were added, the mixture was stirred for 4 h, another 5 equiv. of 2M aqueous sodium hydroxide solution were added, the mixture was stirred in a microwave oven at 110°C/300 Watt for 30 min, 10 equiv. of 2M aqueous sodium hydroxide on were added and the mixture was then heated in a microwave oven at 120°C/300 Watt for 60 min and at 130°C/300 Watt for 60 min), 100 mg (0.26 mmol) of 17-(5-fluoropyridinyl)&stra- ),16-tetraenecarboxylic acid and 84 mg of tert—butyl (S)aminobutyrate were converted into 24 mg (20% of theory) of the title compound.
C23H31FN203 (462.6). MS-ES+ mass found: 462.23. lH-NMR (400MHz, fi): 6 [ppm]= 1.02 (s, 3H), 1.16 (d, 3H), 1.38 - 1.68 (m, 4H), 1.76 (td, 1H), 1.87 - 2.24 (m, 2H), 2.27 - 2.46 (m, 4H), 2.51 - 2.61 (m, - 2.01 (m, 1H), 2.09 1H), 2.82 - 6.31 (m, 1H), 7.34 (d, 1H), 7.50 - 7.61 (m, - 3.00 (m, 2H), 4.31 (spt, 1H), 6.27 2H), 7.70 (dt, 1H), 8.16 (d, 1H), 8.46 (d, 1H), 8.50 — 8.54 (m, 1H), 12.2 (br. s., 1H).
Example 13 ({[17-(S-Fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}amino)— butanoic acid Page 46 Analogously to Examplel (in step B, an onal 5 equivalents of 2M aqueous sodium hydroxide solution were added and the e was stirred at 50°C for 30 h), 100 mg (0.26 mmol) of l7-(5-fluoropyridinyl)estra-1,3,5(10),l6-tetraenecarboxylic acid and 84 mg of tert-butyl (R)-3—aminobutyrate were converted into 34 mg (28% of theory) of the title compound.
C23H31FN203 ). MS-ES+ mass found: 462.23. 1H-NMR (400 MHz, G): 6 [ppm]= 1.02 (s, 3H), 1.16 (d, 3H), 1.39 - 1.69 (m, 4H), 1.76 (td, 1H), 1.88 - 2.23 (m, 2H), 2.27 - 2.47 (m, 4H), 2.51 - 2.61 (m, - 2.00 (m, 1H), 2.09 1H), 2.82 (spt, 1H), 6.24 - 6.34 (m, 1H), 7.34 (d, 1H), 7.52 — 7.60 (m, - 2.98 (m, 2H), 4.32 2H), 7.70 (dt, 1H), 8.15 (d, 1H), 8.46 (d, 1H), 8.50 - 8.54 (m, 1H), 12.1 (br. s., 1H).
Example 14 3-({[17-(5-Methoxypyridin-3—yl)estra-1,3,5(10),l6-tetraenyl]carbonyl}amino)—2,2- dimethylpropanoic acid Analogously to Example 1 (step B was carried out by stirring at 50°C for 7 h), 100 mg (0.26 mmol) of 17-(5-methoxypyridinyl)estra—1,3,5(10),]6-tetraenecarboxylic acid and 75 mg (0.51 mmol) of ethyl 3-amino-2,2-dimethylpropanoate were converted into 12 mg (10% of theory) ofthe title compound.
C30H36N204 (488.63). MS-ES+ mass found: 488.27. lH-NMR (300 MHz, DMSO-d6): 5 [ppm]= 0.98 (s, 3H), 1.06 (s, 6H), 1.31 - 1.82 (m, 5H), 1.84 — 1.97 (m, 1H), 2.00 - 2.19 (m, 2H), 2.20 - 2.40 (m), 2.80 — 2.95 (m, 2H), 3.36 — 3.38 (m, partially obscured by water signal), 3.81 (s, 3H), 6.16 (s., 1H), 7.20 - 7.37 (m, 2H), 7.46 - 7.63 (m, 2H), 8.09 - 8.27 (m, 3H).
Page 47 Example 15 N-{[17-(5-Methoxypyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-,6—alanine ously to el (step B was carried out by stirring at 50°C for 7 h), 100 mg (0.26 mmol) of 17-(5-methoxypyridin—3-yl)estra—1,3,5(10),16-tetraene-3—carboxylic acid and 79 mg (0.51 mmol) of ethyl fl-alaninate hydrochloride were converted into 64 mg (54% of theory) of the title compound.
C28H32N204 (460.58). MS-ES+ mass found: 460.24. 1H-NMR (300 MHz, DMSO‘dé): 5 [ppm]= 0.98 (s, 3H), 1.38 - 1.78 (m, 5H), 1.85 - 1.96 (m, 1H), 2.04 - 3.50 (m, 2H), 3.81 - 2.98 (m, 2H), 3.34 - 2.41 (m, 3H), 2.76 - 2.18 (m, 2H), 2.21 (s, 3H), 6.14 - 7.28 (m, 1H), 7.31 - 6.18 (m, 1H), 7.23 (d, 1H), 7.46 - 7.63 (m, 2H), 8.16 (d, 1H), 8.20 "(d, 1H), 8.38 (t, 1H), 12.2 (br. s., 1H).
Example 16 N-{[l7-(5-Methoxypyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-N-methyl-fl- alanine Page 48 39 mg (1.0 equiv.) of l-hydroxy-lH-benzotriazole hydrate, 98 mg (2.0 equiv.) of l-[3- (dimethylamino)propyl]ethylcarbodiimide hydrochloride and 0.11 ml of ylamine were added to a mixture of 100 mg (0.26 mmol) of 17-(5—methoxypyridin-3—yl)estra- l,3,5(10),16-tetraenecarboxylic acid and 82 mg (2 equiv.) of tert-butyl N-methyl-fl- alaninate in 3 ml of THF and 1 ml of DMF, and the mixture was stirred at RT for 72 h. The mixture was diluted with water and extracted three times with ethyl e, and the extracts were concentrated. 4 ml of dichloromethane and 1 ml of trifluoroacetic acid were added to the residue, and the mixture was stirred at room temperature for 17 h. The mixture was concentrated giving, after purification of the residue by preparative HPLC, 66 mg of the title compound.
C29H34N204. (474.61). MS-ES+ mass found: 474.25. 1H-NMR (300 MHz, DMSO-ds): 8 [ppm]= 0.99 (s, 3H), 1.38 - 1.78 (1n, 5H), 1.82 — 1.96 (m, 1H), 2.03 - 2.18 (m, 2H), 2.21 - 2.43 (m, 3H), 2.79 - 2.93 (m, 5H), 3.42 (br. s., 1H), 3.57 (br. s., 1H), 3.81 (s, 3H), 6.16 (s, 1H), 6.99 — 7.31 (m, 2H), 8.13 - 8.22 (m, - 7.14 (m, 2H), 7.23 2H), 12.3 (br. s., 1H).
Example 17 -(Pyrimidin-S-yl)estra-l,3,5(l0),l6-tetraenyl}carbonyl}-fl-alanine Analogously to Examplel (step B was carried out by stirring at 50°C for 18 h), 100 mg (0.28 mmol) of 17—(pyrimidin-5—yl)estra—l,3,5(10),16-tetraene—3-carboxylic acid and 85 mg (2.0 ) of ethyl fl-alaninate hydrochloride were converted into 63 mg (50% of theory) of the title compound.
C26H29N3O3 (431.5). MS—ES+ mass found: . 1H-NMR (300 MHz, DMSO-ds): 6 [ppm]= 0.99 (s, 3H), 1.36 - 1.79 (m, 5H), 1.84 - 1.97 (m, 1H), 2.06 - 2.20 (m, 2H), 2.25 - 2.41 (m, 4H), 2.82 - 2.93 (m, 2H), 3.35 - 3.45 (m, 2H), 6.28 - Page 49 WO 45407 6.33 (m, 1H), 7.31 (d, 1H), 7.50 - 7.58 (m, 2H), 8.38 (t, 1H), 8.83 (s, 2H), 9.04 (s, 1H), 12.19 (br. s., 1H).
Example 18 4-({[l7-(Pyrimidinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}amino)butanoic acid Analogously to Example] (step B was carried out by stirring at 50°C for 18 h), 100 mg (0.28 mmol) of 17-(pyrimidinyl)estra-l,3,5(10),16-tetraenecarboxylic acid and 85 mg (2.0 equiv.) of methyl 4-aminobutanoate hloride were converted into 61 mg (47% of theory) of the title compound.
C27H31N303 (445.6). MS-ES+ mass found: 445.24.
‘H-NMR (300 MHz, DMSO-dé): 8 [ppm]= 0.99 (s, 3H), 1.39 - 1.79 (m, 7H), 1.85 - 1.98 (m, 1H), 2.05 - 2.95 (m, 2H), 3.15 - 3.25 (m, 2H), 6.27 - - 2.26 (m, 4H), 2.26 - 2.41 (m, 3H), 2.81 6.34 (m, 1H), 7.31 (d, 1H), 7.50 - 7.61 (m, 2H), 8.34 (t, 1H), 8.83 (s, 2H), 9.04 (s, 1H), 12.04 (br. s., 1H).
Example 19 N-Methyl-N—{[17-(pyrimidin-5—yl)estra-1,3,5(10),16-tetraenyl]carbonyl}-[)‘-alanine Page 50 42 mg (1 equiv.) of l-hydroxy-lH-benzotriazole hydrate, 106 mg (2.0 ) of l-[3- hylamino)propy1]ethylcarbodiimide hydrochloride and 0.12 ml of tn'ethylamine were added to a mixture of 100 mg (0.26 mmol) of 17-(pyrimidin—5-yl)estra—1,3,5(10),16- tetraenecarboxy1ic acid and 88 mg (2 equiv.) of tert-butyl N-methyl-fl-alaninate in 3 ml of THF and 1 ml of DMF, and the mixture was stirred at RT for 72 h. The mixture was diluted with water and extracted three times with ethyl e, and the extracts were concentrated. 3 ml of dichloromethane and 1 ml of trifluoroacetic acid were added to the residue, and the mixture was stirred at room temperature for 72 h. The e was concentrated giving, after purification ofthe residue by preparative HPLC, 56 mg of the title compound.
C27H31N303 (445.6). MS-ES+ mass found: 445.24. 1H-NMR (300 MHz, DMSO-ds): 6 [ppm]= 1.00 (s, 3H), 1.36 - 1.77 (m, 5H), 1.85 - 1.94 (m, 1H), 2.07 - 2.20 (m, 2H), 2.26 - 2.5 (m, obscured), 2.80 - 2.92 (m, 5H), 3.42 (br. s., 1H), 3.57 (br. s., 1H), 6.27 — 6.33 (m, 1H), 7.02 - 7.11 (m, 2H), 7.29 (d, 1H), 8.83 (s, 2H), 9.04 (s, 1H), 12.3 (br. s, 1H).
Example 20 2,2-Dimethyl({[17-(pyrimidin-S-yl)estra-l,3,5(10),l6-tetraenyl]carbonyl}amino)- propanoic acid H3C H HO N Analogously to Examplel (step B was carried out by stirring at 50°C for 5 h), 100 mg (0.28 mmol) of 17—(pyrimidin—5-yl)estra-1,3,5(10),]6-tetraene—3-carboxylic acid and 81 mg (0.55 mmol) of ethyl o-2,2-dimethylpropanoate were converted into 10mg (8% of theory) of the title compound.
C28H33N303 (459.6). MS-ES+ mass found: 459.25. lH-NMR (600 MHz, DMSO'db): 5 [ppm]= 1.02 (s, 3H), 1.09 (s, 6H), 1.42 - 1.50 (m, 1H), 1.53 — 1.68 (m, 3H), 1.77 (td, 1H), 1.91 - 1.97 (m, 1H), 2.13 - 2.20 (m, 2H), 2.31 - 2.39 (m, Page 51 2H), 2.41 - - 2.47 (m, 1H), 2.89 — 2.94 (m, 2H), 3.40 (d, 2H), 6.33 (dd, 1H), 7.34 (d, 1H), 7.53 7.59 (m, 2H), 8.16 — 8.21 (m., 1H), 8.85 (s, 2H), 9.07 (s, 1H), 12.25 (br. s., 1H).
Example 21 N-({17-[5-(Trifluoromethyl)pyridinyl]estra—1,3,5(l0),16—tetraenyl}carbonyl)-fl- alanine Analogously to Examplel (step B was carried out by stirring at 50°C for 18 h), 100 mg (0.23 mmol) of 17-[5-(trifluoromethyl)pyridinyl]estra-1,3,5(10),16-tetraenecarboxylic acid and 72 mg (2.0 ) of ethyl fl-alaninate hydrochloride were converted into 65 mg (56% of theory) ofthe title compound.
C28H29F3N203 (498.6). MS-ES+ mass found: 498.21. 1H-NMR (300 MHz, s): 5 [ppm]= 1.01 (s, 3H), 1.35 - 1.69 (m, 4H), 1.76 (td, 1H), 1.84 - 2.96 (m, 2H), 3.35 - 3.53 (m, - 2.00 (m, 1H), 2.03 - 2.21 (m, 2H), 2.24 - 2.41 (m), 2.78 2H), 6.33 — 6.38 (m, 1H), 7.31 (d, 1H), 7.47 - 7.62 (m, 2H), 8.03 (s, 1H), 8.35 (t, 1H), 8.78 - 8.86 (m, 1H), 8.86 - 8.97 (m, 1H), 12.2 (br. s., 1H).
Example 22 N-Methyl—N—({17-[5-(trifluoromethyl)pyridinyl]estra-l,3,5(10),l6-tetraen yl}carbonyl)-fi-alanine Page 52 Step A: 36 mg (1 equiv.) of l-hydroxy—lH-benzotriazole hydrate, 90 mg (2.0 equiv.) of 1-[3— (dimethylamino)propyl]ethylcarbodiimide hydrochloride and 98 microlitres of triethylamine were added to a mixture of 100 mg (0.23 mmol) of 17-[5— (trifluoromethyl)pyridinyl]estra-l,3,5(10),l6-tetraenecarboxylic acid and 74 mg (2 equiv.) of tert-butyl N-methyl-B-alaninate in 3 m1 of THF, and the mixture was stirred at RT for 4 h. The mixture was d with water and extracted three times with ethyl acetate, and the extracts were trated.
Step B: 2 ml of dichloromethane and 180 itres of roacetic acid were added, and the mixture was stirred at a bath temperature of 40°C for 18 h. A further 90 microlitres of trifluoroacetic acid were added, and the mixture was stirred at 40°C for 5 h. Water was added, the phases were separated and the aqueous phase was extracted twice with dichloromethane.
The organic phases were concentrated and the residue was d by HPLC (acetonitrile/water/formic acid). This gave 83 mg (69% of theory) of the title compound.
C29H31F3N203 (512.58). MS—ES+ mass found: 512.23. 1H-NMR (300 MHz, DMSO-dg): 8 [ppm]= 1.01 (s, 3H), 1.36 - 1.51 (m, 1H), 1.52 - 1.81 (m, 4H), 1.84 - 1.98 (m, 1H), 2.04 - 2.21 (m, 2H), 2.25 - 2.40 (m), 2.79 - 2.96 (m, 5H), 3.42 (br. s.), 3.55 (br. s.), 6.35 (s, 1H), 7.00 - 7.15 (m, 2H), 7.28 (d, 1H), 8.03 (s, 1H), 8.81 - 8.87 (m, 1H), 8.87 - 8.95 (m, 1H), 12.3 (br. s., 1H).
Example 23 N-{[17-(5-Fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-L-proline Page 53 ously to Example 22, 100 mg (0.26 mmol) of 17-(5-fluoropyridinyl)estra- 1,3,5(10),16-tetraene—3-carboxylic acid were reacted with 91 mg (2.0 equiv.) of tert-butyl L- prolinate. Purification by preparative HPLC gave 65 mg (50% of theory) of the title compound.
C29H31FN203 (474.6). MS-ES+ mass found: 474.23.
]H-NMR (300 MHz, DMSO'dfi): 8 [ppm]= 1.00 (s, 3H), 1.39 - 1.94 (m), 2.05 - 2.43 (m), 2.77 — 2.94 (m, 2H), 3.40 - 3.59 (m, 2H), 4.27 ~ 4.40 (m, 1H), 6.27 (s., 1H), 7.04 - 7.34 (m, 3H), 7.64 - 7.73 (m, 1H), 8.43 (d, 1H), 8.49 (s, 1H), 12.5 (br. s., 1H).
The title compound was analysed by analytical HPLC: system: Waters: ce 2695, DAD 996 Column: Chiralpak AS-RH Sum 150x4.6 mm Solvent: H20 (0.1% by volume formic acid)/acetonitrile 50:50 (v/v) p...
Page 54 Example 24 N-{[17-(S-Fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-D-proline Analogously to Example 22, 100 mg (0.26 mmol) of 17-(5-fluoropyridiny1)estra- 1,3,5(10),16-tetraenecarboxylic acid were reacted with 91 mg (2.0 equiv.) of tert-butyl D- prolinate. Purification by preparative HPLC gave 66 mg (52% of theory) of the title compound.
C29H31FN203 ). MS-ES+ mass found: . 1H-NMR (300 MHz, DMSO-ds): 6 [ppm]= 1.00 (s, 3H), 1.34 - 1.97 (m), 2.05 — 2.43 (m), 2.75 — 2.94 (m, 2H), 3.42 - 3.59 (m, 2H), 4.25 - 4.40 (m, 1H), 6.27 (s., 1H), 7.02 - 7.36 (m, 3H), 7.68 (d, 1H), 8.43 (d, 1H), 8.49 (s, 1H), 12.5 (br. s., 1H).
The title nd was analysed by analytical HPLC: Waters: Alliance 2695, DAD 996 Chiralpak AS-RH 5pm 150x4.6 mm Solvent H20 (0.1% by volume formic acid)/acetonitri1e 50:50 (v/v) 1.0 mg/ml ethanol/methanol 2:1 Page 55 Example 25 4-({[1 lfl—Fluoro—l7-(5-fluoropyridin—S-yl)estra-1,3,5(10),16-tetraenyl]carbonyl}- butanoic acid Analogously to Example 1, 100 mg of 1lfl-fluoro-l7—(5-fluoropyridiny1)estra—1,3,5(]O),l6- tetraenecarboxylic acid and 78 mg (2.0 equiv.) of methyl 4-amin0butanoate hydrochloride were converted into 80 mg (66% of theory) of the title compound.
C28H30F2N203 (480.6). MS-ES+ mass found: .
]H-NMR (400 MHz, DMSO'dé): 5 [ppm]= 1.14 (s, 3H), 1.40 — 1.55 (m, 1H), 1.70 (quin, 2H), 1.74 - 2.03 (m, 4H), 2.13 - 2.27 (m, 3H), 2.27 - 2.37 (m, 1H), 2.49 - 2.60 (m, 1H), 2.60 — 2.77 (m, 1H), 2.81 - 2.97 (m, 2H), 3.22 (q, 2H), 5.58 - 5.80 (m, 1H), 6.21 - 6.34 (m, 1H), 7.40 (d, 1H), 7.48 - 7.61 (m, 2H), 7.72 (dt, 1H), 8.36 (t, 1H), 8.45 (d, 1H), 8.50 (s, 1H), 12.0 (br. s., 1H).
Example 26 N-{[17—(5-Fluoropyridin-S-yl)-15a-hydroxyestra-l,3,5(l0),l6-tetraenyl]carbonyl}—N- methyl-fl-alanine Page 56 2012/068803 A 100 m1 Erlenmeyer flask which contained 20 ml of an aqueous nt solution comprising 1% of maize steeping liquor and 1% of soybean meal (adjusted to pH 6.2) which had been sterilized in an autoclave at 121°C for 20 minutes was inoculated with 0.2 m1 of a DMSO/ice culture of the strain Calonectrz'a decora (ATCC No. 14767) and shaken at 21°C on a rotary shaker at 165 tions per minute for 48 hours. A 500 ml Erlenmeyer flask which had been charged with 100 ml of sterile medium of the same final composition as described for the preculture was inoculated with 8 m1 of this ture. This flask was shaken at 21°C on a rotary shaker at 165 rotations per minute for 48 hours. Two 21 Erlenmeyer flasks each containing 1 l of a sterile nutrient on comprising 3% glucose monohydrate, 1% ammonium chloride, 0.2% sodium nitrate, 0.1% potassium dihydrogen phosphate, 0.2% dipotassium hydrogen phosphate, 0.05% potassium chloride, 0.05% magnesium sulphate heptahydrate and 0.002% iron(II) sulphate heptahydrate were inoculated with in each case 50 m] of this ture. Afier a growth phase of 6 hours at 27°C on a rotary shaker at 165 revolutions per minute at a temperature of 27°C, a solution of 50 mg of N—{[17-(5- yridin-3 -yl)estra-1,3,5(10),16-tetraeny1]carbony1}-N-methyl-fl-alanine in 10 ml of DMF was divided into the two flasks. The flasks were shaken for a further 43 hours and then worked up. The two culture broths were combined and extracted with l l of isobutyl methyl ketone at 40 revolutions per minute in a 5 1 glass extracting vessel for 19 hours. The c phase was dried over sodium sulphate and concentrated to dryness. The residue was washed with methanol to remove the silicone oil. This gave 328 mg of a crude product. The crude product was absorbed on diatomaceous earth and chromatographed: method: Biotage Isolera, g SNAP column, solvent: gradient from 2 to 20% methanol in ethyl e (1% of l acetic acid added). This gave 42 mg of the target compound.
HPLC Rt = 4.8 min HPLC conditions: A: water with 0.05% formic acid; B: acetonitrile with 0.1% formic acid; gradient: 0 min: 60:40 A/B; 12 min: 30:70 NE; flow rate: 0.8 ml/min; column: Luna C18 (2) 5n 125x46; detection wavelengths: 244 nm 1H-NMR (400 MHz, DMSO-d6): 8 [ppm]= 1.08 (s, 3 H), 1.50 — 1.58 (m, 2 H), 1.61 — 1.67 (m, 2 H), 1.76 — 1.85 (m, 1 H), 2.08 — 2.12 (m, l H), 2.30 — 2.35 (m, 2 H), 2.40 — 2.45 (m, 1 H), 2.55 (2H superimposed by DMSO signal), 2.85 — 2.89 (m, 2 H), 2.91 (s, 3 H), 3.45 (br. s, 1 H), 3.62 (br. s, 1 H), 4.62 (d, 1 H), 4.95 (br. s, 1 H), 6.15 (s, 1 H), 7.05 (s, 1 H), 7.11 (d, 1 H), 7.31 (d, 1 H), 7.71 (d, l H), 8.49 (d, 1H), 8.51 (s, 1 H), 12.1 (br. s, 1 H).
Page 57 Example 27 N-{ [1 7-(5-Fluoropyridinyl)—lSfl-hydroxyestra-1,3,5(10),16-tetraenyl] carbonyl}-N- methyl-fl-alanine: A 100 ml Erlenmeyer flask which ned 20 m1 of an aqueous nt solution comprising 3% of glucose monohydrate, 1% maize steeping liquor, 0.2% sodium nitrate, 0.1% potassium dihydrogen phosphate, 0.2% dipotassium hydrogen ate, 0.05% potassium chloride, 0.05% magnesium sulphate heptahydrate and 0.002% iron(II) sulphate heptahydrate (adjusted to pH 6.0) which had been sterilized in an autoclave at 121°C for 20 minutes was inoculated with 0.2 ml of a DMSO/ice culture of the strain Mucor plumbeus (CBS No. 29563) and shaken at 27°C on a rotary shaker at 165 revolutions per minute for 65 hours. A 500 m1 Erlenmeyer flask which had been charged with 100 m1 of sterile medium of the same final composition as described for the preculture was inoculated with 8 m1 of this preculture. This flask was shaken at 27°C on a rotary shaker at 165 rotations per minute for 72 hours. Two 2 1 Erlenmeyer flasks each containing 1 1 of a sterile nutrient solution comprising 3% glucose monohydrate, 1% ammonium chloride, 0.2% sodium nitrate, 0.1% potassium dihydrogen ate, 0.2% dipotassium hydrogen phosphate, 0.05% ium chloride, 0.05% magnesium sulphate heptahydrate and 0.002% iron(II) sulphate heptahydrate were ated with in each case 50 ml of this preculture. After a growth phase of 6 hours at 27°C on a rotary shaker at 165 revolutions per minute at a temperature of 27°C, a solution of 50 mg ofN-{[17- (5-fluoropyridinyl)estra-1,3,5(l0),16-tetraenyl]carbony1}-N-methyl-fl-alanine in 10 ml of DMF was divided into the two flasks. The flasks were shaken for a further 43 hours and then worked up. The two e broths were combined and extracted with 1 1 of isobutyl methyl ketone at 40 revolutions per minute in a S 1 glass extracting vessel for 19 hours. The organic phase was dried over sodium sulphate and concentrated to s. The residue was washed with methanol to remove the ne oil. This gave 236 mg of a crude product as a Page 58 2012/068803 brown oil. The crude product was absorbed on diatomaceous earth and chromatographed: instrument: Biotage Isolera, 10 g SNAP column, solvent: nt from 2 to 20% methanol in ethyl acetate (1% of glacial acetic acid added). This gave 35 mg of the target compound.
HPLC Rt = 5.4 min HPLC conditions: A: water with 0.05% formic acid; B: acetonitrile with 0.1% formic acid; gradient: 0 min: 60:40 A/B; 12 min: 30:70 NE; flow rate: 0.8 ml/min; column: Luna C18 (2) 5p 125x46; Detection wavelengths: 244 nm 1H-NMR (400 MHz, DMSO-d6): 6 [ppm]= 1.28 (s, 3 H); 1.38 — 1.60 (m, 4 H); 1.69 — 1.78 (m, 1 H); 2.01 — 2.08 (m, 1 H); 2.20 — 2.28 (m, 1 H); 2.30 — 2.40 (m, 1 H); 2.55 (2H superimposed by DMSO signal); 2.85 — 2.90 (m, 5 H), 3.10 (s, 1 H); 3.45 (br. s, 1 H); 3.57 (br. s, 1 H); 4.50 (s, 1 H); 4.69 (br. s, 1 H); 6.30 (s, 1 H); 7.05 (s, 1 H); 7.08 (d, 1 H); 7.28 (d, 1 H); 7.71 (d7, 1 H); 8.47 (d, 1 H); 8.52 (s, l H); 12.1 (br. s, 1 H).
Example 28 yl—N-{[17-(6-methylpyridazin—4-yl)estra-l,3,5(10),16-tetraenyl]carbonyl}-fl- alanine 42 mg of 17-(6—methy1pyridazin—4-yl)estra-1,3,5(10),16-tetraenecarboxylic acid (impure) and 36 mg of tert-butyl N-methyl-fl-alaninate (2 equiv.) were ved in 2.5 m1 of THF and 0.5 ml of DMF. 43 mg of 1—[3-(dimethylamino)propyl]ethylcarbodiimide hydrochloride (EDC), 17 mg of 1-hydroxy-1H-benzotriazole hydrate and 0.047 ml of triethylamine were added, and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted three times with ethyl e. The combined organic phases were concentrated, 2 m1 of dichloromethane and 0.5 m1 of trifluoroacetic acid were added to Page 59 the e and the mixture was stirred at room temperature for 6 h. The mixture was concentrated and the product was purified by preparative HPLC. This gave 18 mg of the title compound.
C28H33N303 (459H59) MS-ES+ mass found: .
'H-NMR (400 MHz, 6): 6 [ppm]= 1.02 (s, 3H), 1.35 - 1.77 (m, 5H), 1.84 — 1.95 (m, 1H), 2.07 - 2.42 (m, 6H), 2.58 (s, 3H), 2.78 - 2.95 (m, 5H), 3.41 (br. s), 3.57 (br. s), 6.54 — 6.59 (m, 1H), 7.02 - 7.13 (m, 2H), 7.29 (d, 1 H), 7.49 (d, 1H), 9.10 (d, 1H), 12.3 (br. s, 1H).
Example 29 N—Methyl—N-{[17-(pyridinyl)estra—l,3,5(10),16-tetraenyl]carbonyl}-fl-alanine 100 mg of l7-(pyridinyl)estra-1,3,5(10),16-tetraenecarboxylic acid and 89 mg of tert- buty] N-methyl-fi-alaninate (2 equiv.) were dissolved in 3 ml of THF and 0.5 m1 of DMF. 107 mg of 1-[3-(dimethy1amino)propyl]ethylcarbodiimide hydrochloride (EDC), 43 mg of l-hydroxy-lH-benzotriazole hydrate and 0.116 ml of triethylarnine were added, and the mixture was d at room temperature for 18 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were concentrated, 3 m1 of dichloromethane and 1 m1 of trifluoroacetic acid were added to the residue and the mixture was stirred at room temperature for 20 h. The mixture was concentrated and the product was d by preparative HPLC. This gave 78 mg ofthe title compound.
C23H32N203 (444.58). MS-ES+ mass found: 444.24. lH-NMR (400 MHz, DMSO—ds): 5 [ppm]= 0.99 (s, 3H), 1.37 — 1.67 (m, 4H), 1.73 (td, 1H), 1.86 - 1.94 (m, 1H), 2.06 - 2.17 (m, 2H), 2.24 - 2.45 (m, 3H), 2.80 - 2.93 (m, 5H), 3.42 (br. s.), 3.57 (br. s.), 6.12 (dd, 1H), 7.02 - 7.11 (m, 2H), 7.26 - 7.35 (m, 2H), 7.77 (dt, 1H), 8.42 (dd, 1H), 8.59 (d, 1H), 123 (br. s., 1H).
Page 60 Example 30 4-({[17-(5-Methoxypyridin-3—yl)estra—1,3,5(10),l6-tetraenyl]carbonyl}amino)butanoic acid Analogously to Example 1, 100 mg (0.26 mmol) of 17-(5-methoxypyridin—3—y1)estra- 1,3,5(10),16-tetraenecarboxylic acid and 79 mg of methyl 4-aminobutanoate hydrochloride were converted into 64 mg (53% of theory) of the title compound.
C29H34N204 (474.61). MS-ES+ mass found: 474.25. 1H-NMR (300 MHz, DMSO-d6): 6 [ppm]= 0.99 (s, 3H), 1.38 - 1.78 (m, 7H), 1.86 - 1.96 (m, 1H), 2.04 - 2.43 (m, 7H), 2.83 - 2.92 (m, 2H), 3.15 - 3.26 (m, 2H), 3.81 (s, 3H), 6.16 (s, 1H), 7.23 - 7.34 (m, 2H), 7.51 - 7.59 (m, 2H), 8.16 (d, 1H), 8.20 (d, 1H), 8.33 (t, 1H), 12.0 (br. s., 1H).
Pharmacological examination of the compounds according to the invention in vitro Example 31 (AKRlCS-inhibitory ty) The AKR1C3-inhibitory activity of the nces of the present ion was ed in the AKRl C3 assay described in the paragraphs below.
Essentially, the enzyme activity is measured by quantification of the Coumberol from Coumberone (Halim, M., Yee, D.J., and Sames, D., J. AM. CHEM. SOC. 130, 14123—14128 (2008) and Yee, D.J., Balsanek, V., Bauman, D.R., Penning, T.M., and Sames, D., Proc. Natl.
Acad. Sci. USA 103, 13304 — 13309 (2006)). In this test, the increase of the highly fluorescent Coumberol by NADPH- (nicotinamide adenine dinucleotide phosphate)- dependent ion of the non-fluorescent Coumberone by AKR1C3 can be determined.
Page 61 The enzyme used was inant human AKR1C3 keto reductase family 1 member C3) (GenBank Accession No. NM_003739). This was expressed in E. coli as GST (glutathione S transferase) fusion protein and purified by glutathione Sepharose affinity chromatography. The GST was removed by digestion with thrombin and subsequent size exclusion chromatography (Dufort, I., Rheault, P., Huang, XF., Soucy, P., and Luu-The, V., Endocrinology 140, 568-574 (1999)).
For the assay, 50 n1 of a ld concentrated solution of the test substance in DMSO were pipetted into a black low-volume ll microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2.0 ul of a solution of AKR1C3 in assay buffer [50 mM potassium phosphate buffer pH 7, lmM DTT, 0.0022% (w/v) Pluronic F-127, 0.01% BSA (w/v) and protease inhibitor cocktail ete, 'ee Protease Inhibitor Cocktail from ] were added and the mixture was incubated for 15 min to allow pre-binding of the substances to the enzyme prior to the enzyme reaction. The enzyme reaction was then started by addition 3 ul of a solution of NADPH (16.7 uM 9 final concentration in 5 ul of assay volume is 10 uM) and Coumberone (0.5 uM 9 final concentration in 5 ul of assay volume is 0.3 uM) in assay buffer, and the resulting mixture was incubated at 22°C for the reaction time of 90 min. The concentration of the AKR1C3 was adapted to the respective activity of the enzyme preparation and adjusted such that the assay was carried out in the linear range.
Typical concentrations were in the region of 1 nM. The reaction was stopped by addition of 5 ul of a stop on consisting of the inhibitor EM-1404 [F. Labrie et al. US Patent 6,541,463, 2003] (211M 9 final concentration in 5 ul of assay volume is 1 uM). The fluorescence of the Coumberole was then measured at 520 nm (excitation at 380 nm) using a suitable measuring instrument (Pherastar fi'om BMG Labtechnologies). The intensity of the fluorescence was used as a measure of the amount of Coumberole formed and thus of the enzyme activity of AKR1C3. The data were normalized (enzyme reaction without inhibitor = 0 % inhibition; all other assay components, but no enzyme = 100% inhibition). Usually, the test substances were tested on the same microtiter plate at 11 different trations in the 12.9 nM, range from 20 pM to 96.8 pM (20 nM, 5.9 nM, 1.7 nM, 0.5 nM, 0.15 nM, 44 nM, 3.8 nM, 1.1 nM, 0.3 nM and 96.8 pM, the on series were prepared prior to the assay on the level of the lOO-fold concentrated solution by serial 1:3 dilutions with 100% DMSO) in double for each concentration, and the ICso values were calculated using a 4-parameter fit.
As described, the pharmacological substances d were examined for their inhibitory activity on the AKR1C3 enzyme (see Table 1). For the major part of the range of structures Page 62 claimed, these compounds show a strong inhibition of AKR1C3 in vitro (IC50 values < 50 nM) and in most cases even 1050 values < 20 nM.
Table 1: Inhibition of AKR1C3 of the compounds ing to the invention (for the major part of the compounds, the values oftwo experimental determinations are stated) Exemplary AKR1C3 enzyme Exemplary AKR1C3 enzyme Exemplary AKR1C3 enzyme compound inhibition 1C5o nd inhibition ICso compound inhibition ICso [nmol/l nmol/l nmol/l “nu—— --_————-————— --——-— -_———— -————— -_——-_ n- — —— “—“—— -_———— -——“-_ —————_ n—n—————nm--— -“—_-_ n——_—— nun—-—nun-— —“——-— Example 32 (Inhibition of Cyp17A1) CYP17A1 (synonym l7a-hydroxylase/17.20-1yase) is an enzyme which adds a hydroxyl group to position 17 of the steroidal D ring of pregnenolone and terone, thus forming l7a-hydroxyprogesterone and l7a-hydroxypregnenolone. uently, dehydroepiandro- sterone and androstendione are formed. The known CYP17A1 inhibitor abiraterone, for Page 63 example, is used for the therapy of metastased, castration-refractory prostate carcinoma after failure of a docetaxel-based chemotherapy (Urologe 2010, 49, 64—68). erone blocks the androgen synthesis and oestrogen synthesis in the entire body and thus lowers the hormone production in a non-tissue-specific manner, which leads to unwanted side-effects (of. press release of the FDA, US. Food and Drug Admistration dated 28 April 2011).
Surprisingly, it has been found that the compounds according to the invention inhibit CYP17A1 only very weakly, if at all, although they have an aromatic en-containing heterocycle in position 17 of the steroidal skeleton.
Assay description: The inhibition of CYP17A1 by the test compounds was evaluated using a recombinant J. Steroid Biochem. enzyme. Human CYP17A1 was expressed in E. coli (Ehrner, P. B. et al.; M01. Biol, 75, 57—63 (2000)). The microsomal fraction and 140 uL of phosphate buffer (50 mM Na phosphate, 1 mM MgC12, 0.1 mM EDTA, 0.1 mM dithiothreitol, pH 7.4) were preincubated separately with a mixture of progesterone (24.95 uM) and gesterone (0.05 uM, 101.3 Ci/mmol), 50 uM of an NADPH regeneration system (in phosphate buffer with 10 mM NADP+, 100 mM glucose 6-phosphate and 2.5 U of glucose phate dehydrogenase) and the appropriate test substances (in 5 ul of DMSO) at 37°C for 5 minutes.
The reaction was started by on of the enzyme and, afier 30 minutes of incubation at 37°C, stopped by on of 50 ul of 1N hydrochloric acid.
The steroids were extracted with ethyl acetate. Afier evaporation of the organic phase, the steroids were taken up in itrile. 16a-Hydroxyprogesterone, 17a-hydroxyprogesterone and progesterone were separated using acetonitrile/water (45:55) as mobile phase on a C18 reverse-phase tography column (Nucleodur C18 Gravity, 3 pm, Macherey-Nagel, Diiren, Germany) on an HPLC system (Agilent 1100 Series, Agilent Technologies, Waldbronn, Germany). Detection and quantification of the steroids was d out using a radio flow detector (Berthold Technologies, Bad d, Germany). The inhibition was calculated using the a below: %(17a — hydroxyprrgesterone+ 16a — hydroxyprrgcsterond (Voinhibition . 100 %(17o: — hydroxyprcgesterone+ 16a — hydroxyprrgesterona + termsterond Each value was calculated from at least three independent experiments. The final ICso value was calculated as the mean of 3 or 4 independent ICso values.
Page 64 The compounds according to the invention show no or an only very weakly nced inhibition of CYP17A1 (Table 2) with ICso values of more than 10 uM compared to the known CYP17A1 inhibitor abiraterone (employed as free base).
Table 2: Inhibition of human CYP1 7 Exemplary ICso :I: SD (uM) nd CYPl7 200200 .19:t 1.58 a% Inhibition at a concentration of 200 uM substance Example 33 (Solubility in aqueous buffer pH 6.5): Determination of the thermodynamic lity in aqueous buffer pH 6.5 (shake-flask method) The thermodynamic solubility was determined according to the shake-flask method [literaturez Edward H. Kems and Li Di (2008) Solubility Methods in: Drug-like Properties: Concepts, Structure Design and Methods, p276—286. Burlington, MA, Academic Press].
Here, a saturated solution of the active compound in buffer pH 6.5 was prepared and stirred for 24 h to ensure that an equilibrium between the solid and the substance in solution had formed. The solution was then centrifuged, and the tration of the solution obtained was quantified with the aid of a calibration line.
For the sample, 2 mg of solid substance were weighed out accurately into a 4 m1 glass bottle. 1 m1 of phosphate buffer pH 6.5 was added. This solution was stirred on a stirrer at room temperature for 24 h. The solution was then centrifuged. To prepare the comparison for the calibration, 2 mg of solid substance were weighed out accurately and dissolved in 30 ml of acetonitrile. After a short ultrasound treatment, the solution was d with water to 50 m1.
Sample and comparison were fied using HPLC with UV detection. Each sample was injected three times per injection volume (5 and 50 pl). For the ison, three injection volumes (5 u], 10 ul and 20 ul) were injected.
Page 65 The following chromatography conditions were chosen: HPLC column: Xterra MS C18 2.5 pm 4.6 x 30 mm Injection volumes: sample: 3x5 pl and 3x50 p1 comparison: 5 pl, 10 pl, 20 pl Flow rate: 1.5 ml/min Mobile phase: acidic gradient: A: water/0.01% trifluoroacetic acid (TFA) B: acetonitrile/0.01% TFA 0 min —) 95%A 5%B 0-3 min ——-> 35%A 65%B, linear nt 3-5 min —) 35%A 65%B, isocratic -6 min —> 95%A 5%B, isocratic UV detector: a wavelength close to the absorption maximum (between 200 and 400 nm) The areas of the sample and comparison injections and the calculation of the lity (in mg/l) were determined using the HPLC e (Waters Empower 2 FR).
For the compound according to the invention Example 2, a solubility of 354 mg/l was measured; the known AKRl C3 inhibitor 4 showed a solubility of 0.1 mg/l.
Example 34 (endometriosis model) To examine the in vivo efficacy of the exemplary compound Example 2, an endometn'osis model in common marmosets was used. 4—8 year old female common marmosets were employed (body weight between 340 and 460 g). In these animals, endometriosis was induced by puncturing the uterus during a laparotomy and rinsing with e medium such that e cells entered the abdomen via the upper ducts [Einspanier et a1., MolHum Reprod 2006]. The procedure is repeated after 3 months. Prior to the actual start of the treatment, the animals are subjected to a tomy and examined for the presence of endometn'otic lesions on the bladder, the uterus and the ovaries. 6 weeks later, the treatment was started. Two treatment groups were ed, with a group size of n = 6 animals per group. Group 1 was treated with vehicle (strawberry/banana juice) only, group 2 was treated with the test Page 66 nce administered in the vehicle. 30 mg/kg of the test substance were administered orally once per day. The treatment period was 6 weeks. Immediately after the end of the treatment, a 2“d1aparoscopy was carried out and the number and size of the lesions on uterus, ovaries and bladder was determined again. Since both prior to and afier the treatment, hardly any s were found on the ovaries, the ovaries as type of lesion was not taken into account during the evaluation.
Page 67Page 67

Claims (9)

What we claim is:
1. Compounds of the formula (I) R2 N R6 CH H H R3 N R4 (I) , in which X and Y both represent a C-H group or one of X and Y represents a C-H group, while the other represents a nitrogen atom and R1 and R2 independently of one another represent en, fluorine, chlorine, nitrile, trifluoromethyl, pentafluoroethyl, methoxy, ethoxy, trifluoromethoxy, -OCH2CF3, CH3SO2-, CH3CH2SO2-, -(C=O)CH3, carboxyl, C1-C4-alkyl, hydroxy, -CH2OH, -C(CH3)2OH, , -(C=O)NH-alkyl, -(C=O)N(CH3)2, -SO2NH2, -SO2NHCH3 or -SO2N(CH3)2; provided that when one of X and Y represents a C-H group and the other represents a nitrogen atom, at least one of R1 and R2 is hydrogen; R3 and R4 ent en or one of R3 and R4 represents hydrogen, while the other represents hydroxy, ne, methoxy or ethoxy R5 and R6 represent hydrogen or R5 represents fluorine, hydroxy, methoxy or ethoxy and R6 represents hydrogen or R5 represents hydrogen and R6 represents fluorine and represents hydrogen, C1-C4-alkyl, C3-C6-cycloalkyl, cyclopropylmethyl, trifluoromethyl or 2,2,2-trifluoroethyl and represents -CRaRb –COOH where Ra and Rb independently of one r ent hydrogen, methyl, ethyl or Ra and Rb together represent -(CH2)n- where n = 2, 3, 4 or 5, where up to 4 hydrogen atoms of the CH2 groups may be replaced by fluorine atoms or Ra and Rb together ent -CH2-O-CH2-, -CH2-NH-CH2-, -CH2-N(CH3)-CH2-, 2-O-CH2CH2-, -CH2CH2-NH-CH2CH2-, -CH2CH2-N(CH3)-CH2CH2- or Ra represents hydrogen, methyl or ethyl and Rb together with R7 represents -(CH2)n– where n = 1, 2, 3, 4, where up to 4 hydrogen atoms of the CH2 groups may be replaced by fluorine atoms or Ra together with R7 represents -CH2-O-CH2CH2-, -CH2-N(CH3)-CH2CH2- and Rb represents hydrogen, methyl or ethyl or represents -CRcRd-CReRf-COOH where Rc, Rd, Re, Rf represent hydrogen or Rc, Rd ndently of one another represent methyl, ethyl or together represent -(CH2)n- where n = 2, 3, 4, 5 or 2-O-CH2CH2- and Re, Rf represent hydrogen or Rc, Rd represent en and Re, Rf independently of one another represent methyl, ethyl or together represent n- where n = 2, 3, 4, 5, -CH2CH2-O-CH2CH2-, -CH2CH2-NH-CH2CH2-, -CH2CH2-N(CH3)-CH2CH2- or -CH2-O-CH2- or Rc represents methyl, ethyl, trifluoromethyl and Rd, Re and Rf represent hydrogen or Rc, Rd and Rf represent hydrogen and Re represents methyl, ethyl, trifluoromethyl, hydroxy or methoxy or Rc and Re together represent -(CH2)n- where n = 1, 2, 3 or 4 and Rd and Rf represent hydrogen or represents -CH2-CH2-CHRg-COOH where Rg ents hydrogen or Rg and R7 together ent –CH2- or –CH2CH2- and their ceutically acceptable salts, solvates and es of the pharmaceutically able salts.
2. Compounds according to Claim 1, in which represents hydrogen, fluorine, chlorine, nitrile, methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, trifluoromethyl, -(C=O)CH3 and R2 represents hydrogen, and R3 and R4 represent hydrogen or one of R3 and R4 represents hydrogen, while the other represents hydroxy and represents hydrogen or fluorine and represents hydrogen or C1-C4-alkyl and represents -CRaRb–COOH where Ra and Rb independently of one another represent hydrogen, methyl or ethyl or Ra and Rb together represent -(CH2)n- where n = 2, 3, 4 or 5 or Ra represents hydrogen and Rb together with R7 represents –(CH2)n- where n = 3 or 4 or represents -CRcRd-CReRf-COOH where Rc, Rd, Re, Rf represent hydrogen or Rc, Rd represent en and Re, Rf independently of one r represent methyl, ethyl or together ent -(CH2)n- where n = 2, 3, 4, 5 or -CH2CH2-O-CH2CH2- or Rc represents methyl or ethyl and Rd, Re and Rf represent hydrogen or Rc and Re together represent n- where n = 1, 2, 3 or 4 and Rd and Rf represent hydrogen or represents -CH2-CH2-CHRg-COOH where Rg represents en or Rg and R7 together represent -CH2CH2- and their pharmaceutically acceptable salts, solvates and solvates of the pharmaceutically acceptable salts.
3. Compounds according to Claim 1 or 2, in which represents hydrogen, fluorine, chlorine, nitrile, methoxy, trifluoromethyl and R2 represents hydrogen, and R3 and R4 represent hydrogen or R3 represents hydroxy and R4 ents hydrogen or R3 represents hydrogen and R4 represents hydroxy and represents hydrogen or fluorine and represents hydrogen, methyl or ethyl and represents -CRaRb-COOH where Ra and Rb independently of one another represent hydrogen, methyl or ethyl or Ra represents hydrogen and Rb together with R7 represents –(CH2)n- where n = 3 or 4 or represents -CRcRd-CReRf-COOH where Rc, Rd, Re, Rf represent en or Rc, Rd represent hydrogen and Re, Rf independently of one another represent methyl or ethyl or er represent -(CH2)n- where n = 2, 4, 5 or represent -CH2CH2-O-CH2CH2- or Rc represents methyl and Rd, Re and Rf ent en or Rc and Re er represent -(CH2)n- where n = 3 or 4 and Rd and Rf represent en or represents -CH2-CH2-CHRg-COOH where Rg represents hydrogen or Rg and R7 together represent -CH2CH2- and their pharmaceutically acceptable salts, solvates and solvates of the pharmaceutically acceptable salts.
4. Compounds according to Claim 1, 2 or 3, in which represents hydrogen, fluorine, methoxy, trifluoromethyl and R2 represents hydrogen, and R3 and R4 represent hydrogen or R3 represents hydroxy and R4 represents hydrogen or R3 represents hydrogen and R4 represents hydroxy and represents hydrogen or fluorine and represents hydrogen or methyl and represents -CRaRb–COOH where Ra and Rb independently of one another ent hydrogen or methyl or Ra represents hydrogen and Rb together with R7 represents –(CH2)3- or represents -CRcRd-CReRf-COOH where Rc, Rd, Re, Rf represent hydrogen or Rc and Rd represent hydrogen and Re and Rf represent methyl or together represent -(CH2)n- where n = 2 or 4 or represent 2-O-CH2CH2- or Rc represents methyl and Rd, Re and Rf represent hydrogen or Rc and Re together represent -(CH2)3- and Rd and Rf represent hydrogen or represents -CH2-CH2-CHRg-COOH where Rg represents hydrogen or Rg and R7 represent -CH2CH2- and their pharmaceutically acceptable salts, solvates and es of the pharmaceutically acceptable salts.
5. Compounds ing to any one of Claims 1 to 4 having the names 17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}amino)- methyl]-3,4,5,6-tetrahydro-2H-pyrancarboxylic acid N-{[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-N-methyl-β- alanine 1-[({[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}amino)- methyl]cyclopropancarboxylic acid 1-[({[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}amino)- methyl]cyclopentanecarboxylic acid 3-({[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}amino)-2,2- dimethylpropanoic acid 1-{[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}piperidine ylic acid N-{[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl} methylalanine 4-({[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}amino)butanoic acid N-{[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-β-alanine N-{[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}glycine (1R*,2S*)({[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}- amino)cyclopentanecarboxylic acid (S)({[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}amino)- butanoic acid (R)({[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}amino)- butanoic acid 3-({[17-(5-methoxypyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}amino)-2,2- dimethylpropanoic acid N-{[17-(5-methoxypyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-β-alanine N-{[17-(5-methoxypyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-N-methyl-β- alanine N-{[17-(pyrimidinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-β-alanine 4-({[17-(pyrimidinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}amino)butanoic acid yl-N-{[17-(pyrimidinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-β-alanine 2,2-dimethyl({[17-(pyrimidinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}- amino)propanoic acid N-({17-[5-(trifluoromethyl)pyridinyl]estra-1,3,5(10),16-tetraenyl}carbonyl)-β- alanine N-methyl-N-({17-[5-(trifluoromethyl)pyridinyl]estra-1,3,5(10),16-tetraenyl}- carbonyl)-β-alanine N-{[17-(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-L-proline -(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-D-proline 4-({[11β-fluoro(5-fluoropyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}- amino)butanoic acid N-{[17-(5-fluoropyridinyl)-15α-hydroxyestra-1,3,5(10),16-tetraenyl]carbonyl}- N-methyl-β-alanine N-{[17-(5-fluoropyridinyl)-15β-hydroxyestra-1,3,5(10),16-tetraenyl]carbonyl}- N-methyl-β-alanine N-methyl-N-{[17-(6-methylpyridazinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}- β-alanine N-methyl-N-{[17-(3-pyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}-β-alanine 4-({[17-(5-methoxypyridinyl)estra-1,3,5(10),16-tetraenyl]carbonyl}amino)- butanoic acid and their pharmaceutically able salts, solvates and solvates of the pharmaceutically acceptable salts.
6. Compounds according to any one of Claims 1, 2, 3, 4 or 5 for the treatment and/or prophylaxis of es.
7. Use of a compound according to any one of Claims 1, 2, 3, 4 or 5 for preparing a medicament for the treatment and/or prophylaxis of diseases.
8. Compounds according to any one of Claims 1, 2, 3, 4 or 5 for the treatment and/or prophylaxis of endometriosis, of uterine leiomyomas, of uterine bleeding disorders, of dysmenorrhoea, of prostate carcinoma, of prostate hyperplasia, of acne, of seborrhoea, of hair loss, of premature sexual maturity, of polycystic ovary syndrome, of breast cancer, of lung cancer, of endometrial carcinoma, of renal cell carcinoma, of r carcinoma, of non-Hodgkin lymphomas, of c obstructive pulmonary disease (COPD), of adiposity or of inflammatory pain.
9. ment comprising a compound according to any one of Claims 1, 2, 3, 4 or 5 in ation with one or more compound(s), selected from a list comprising selective oestrogen receptor modulators (SERMs), oestrogen receptor (ER) antagonists, aromatase tors, 17 HSD1 inhibitors, steroid sulphatase (STS) inhibitors, GnRH agonists and
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